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Advances in the management of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis

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• Peer review
• Gabrielle Y Liu , pulmonary and critical care fellow ,
• G R Scott Budinger , professor of medicine , chief of pulmonary and critical care in the Department of Medicine ,
• Jane E Dematte , professor of medicine
• Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University, Chicago, IL, USA
• Correspondence to: J E Dematte j-dematte{at}northwestern.edu

Similarly to idiopathic pulmonary fibrosis (IPF), other interstitial lung diseases can develop progressive pulmonary fibrosis (PPF) characterized by declining lung function, a poor response to immunomodulatory therapies, and early mortality. The pathophysiology of disordered lung repair involves common downstream pathways that lead to pulmonary fibrosis in both IPF and PPF. The antifibrotic drugs, such as nintedanib, are indicated for the treatment of IPF and PPF, and new therapies are being evaluated in clinical trials. Clinical, radiographic, and molecular biomarkers are needed to identify patients with PPF and subgroups of patients likely to respond to specific therapies. This article reviews the evidence supporting the use of specific therapies in patients with IPF and PPF, discusses agents being considered in clinical trials, and considers potential biomarkers based on disease pathogenesis that might be used to provide a personalized approach to care.

Introduction

The term interstitial lung disease (ILD) encompasses a group of diffuse parenchymal lung diseases with varied clinical, radiographic, and pathologic manifestations reflecting their diverse underlying pathobiology. A subset of ILDs have a progressive fibrosing phenotype. Idiopathic pulmonary fibrosis (IPF) almost invariably has this phenotype. However, other ILDs may also develop this and are thereby termed progressive pulmonary fibrosis (PPF), previously known as progressive fibrosing interstitial lung disease (PF-ILD). 1 2 3 4 In this review, we will use PPF to refer specifically to non-IPF ILDs that have a progressive fibrosing phenotype. IPF and PPF share common downstream mechanistic pathways resulting in self-sustaining fibrosis that may be independent of the initial injury or trigger. However, PPF often begins with an inflammatory phase triggered by either an endogenous autoantigen or an exogenous antigen, such as an environmental trigger. 5 6 7 Therefore, making a distinction between the two is important, particularly when designing clinical trials and research studies for PPF. Connective tissue disease associated ILD (CTD-ILD), including rheumatoid arthritis associated ILD (RA-ILD), systemic sclerosis associated ILD (SSc-ILD), and myositis associated ILD, as well as chronic hypersensitivity pneumonitis (cHP), sarcoidosis, idiopathic nonspecific interstitial pneumonia (iNSIP), and unclassifiable ILD, are the ILDs most likely to develop a progressive fibrosing phenotype. However, the proportion of patients with these ILDs who develop this phenotype can vary significantly—from an estimated 13% of patients with fibrotic iNSIP to an estimated 87% of patients with cHP. 8 9

Beyond prognostication, identifying patients with PPF is clinically important because evidence from randomized placebo controlled clinical trials shows that nintedanib can slow decline in lung function in both patients with IPF and those with PPF. 10 11 12 This review summarizes the epidemiology and pathophysiology of IPF and PPF, their currently approved treatments, and promising therapies in the pipeline. It highlights the need for therapeutic trials based on specific biomarkers to develop a more personalized approach to therapy for patients with IPF and PPF in the future.

Sources and selection criteria

We searched PubMed and Ovid MEDLINE databases from 2000 to April 2021 using the following search terms: progressive fibrosing interstitial lung disease, idiopathic pulmonary fibrosis, pulmonary fibrosis, connective tissue disease associated interstitial lung disease, rheumatoid arthritis associated interstitial lung disease, scleroderma interstitial lung disease, systemic sclerosis interstitial lung disease, sarcoidosis, myositis interstitial lung disease, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, unclassifiable interstitial lung disease, biomarkers interstitial lung disease, and biomarkers idiopathic pulmonary fibrosis. We reviewed published management guidelines from websites of professional societies and governmental bodies, including the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), Latin American Thoracic Association (ALAT), UK National Institute for Health and Care Excellence (NICE), Thoracic Society of Australia and New Zealand (TSANZ), and Lung Foundation of Australia (LFA). We also searched clinicaltrials.gov for all active phase 3 clinical trials for the treatment of idiopathic pulmonary fibrosis, as well as all active and completed phase 2 and 3 clinical trials of nintedanib and pirfenidone for the treatment of PF-ILDs/PPF. We included only full length, peer reviewed studies published in English. We prioritized phase 3 randomized controlled trials (RCTs), phase 2 RCTs, systematic reviews with meta-analyses, and observational cohort studies, in that order. Case reports were excluded. We also focused on high quality basic science manuscripts that contribute to the understanding of the pathobiology of pulmonary fibrosis and lung injury repair and the key mechanisms of action underlying the therapies reviewed. We reviewed basic science manuscripts with preclinical studies in mouse models of pulmonary fibrosis that provide insights into the pathobiology of lung fibrosis. We determined the quality of basic science papers by their selection for publication in high impact journals, their reproducibility across laboratories, their citations by other investigators, and qualitative assessment by the authors. The abstracts of more than 250 papers were reviewed by at least one of the authors, and more than 169 papers were reviewed in detail.

After the original search date in April 2021, the ATS/ERS/JRS/ALAT clinical practice guideline on IPF (an update) and PPF in adults was published in May 2022. 4 Therefore, this review was updated to use the term “PPF” rather than “PF-ILD,” as determined by this guideline. We updated the algorithm ( fig 1 ) to include the conditional recommendation that transbronchial lung cryobiopsy may be used as an alternative to surgical lung biopsy for making a histopathologic diagnosis in patients with ILD of undertermined type. We also updated the sections on “Conceptualizing and defining PPF,” “Currently approved therapy for IPF: Antacid therapy,” and “Guidelines” to reflect the updated clinical practice guideline.

Suggested algorithm for the evaluation and management of suspect fibrosing interstitial lung disease (ILD). *†American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines suggest bronchoalveolar lavage (BAL) cellular analysis and surgical lung biopsy or transbronchial lung cryobiopsy in the evaluation of patients in whom IPF is clinically suspected or who have an ILD of uncertain etiology and have a high resolution computed tomography (HRCT) pattern of probable usual interstitial pneumonia (UIP), indeterminate for UIP, or an alternative diagnosis. 13 BAL cellular fluid analysis, surgical lung biopsy, and transbronchial lung biopsy are not recommended in patients in whom idiopathic pulmonary fibrosis (IPF) is clinically suspected and who have an HRCT pattern of UIP. CTD-ILD=connective tissue disease associated interstitial lung disease; DLCO=diffusing capacity of the lung for carbon monoxide; FVC=forced vital capacity; GERD=gastresophageal reflux; iNSIP=idiopathic nonspecific interstitial pneumonia; IPAF=interstitial pneumonia with autoimmune features; LTOT=long term oxygen therapy; PFT=pulmonary function test; PPF=progressive pulmonary fibrosis

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Conceptualizing and defining PPF

The concept of grouping several non-IPF fibrosing ILDs together grew in part out of the recognition that an unmet need existed for treatment options for these lung diseases. Apart from SSc-ILD, robust RCT data to support the use of immunosuppression in fibrosing ILDs have been lacking. Additionally, many patients with fibrosing ILDs progressed despite conventional treatment. However, a challenge to the design of a robust randomized clinical trial to evaluate new therapies was the fact that the prevalence of each individual fibrosing ILD is relatively low. Thus, the term PF-ILD first came into use in 2017 with the design and development of the INBUILD trial (clinicaltrials.org; NCT02999178 ). INBUILD was a randomized, double blind, placebo controlled trial to study the efficacy and safety of nintedanib in patients with ILD diagnoses that were noted to behave similarly to IPF in that they were characterized by progressive pulmonary fibrosis, declining lung function, resistance to immunomodulatory therapies, and early mortality. 1

Before the publication of the ATS/ERS/JRS/ALAT clinical practice guideline on PPF in 2022, PF-ILD had been largely defined by selection criteria for clinical trials. Three randomized clinical trials—INBUILD, 12 RELIEF (German Clinical Trials Register; DRKS00009822), 14 and a phase 2 clinical trial evaluating the use of pirfenidone in patients with progressive fibrosing unclassifiable ILD ( NCT03099187 ) 15 —have proposed criteria for progressive fibrosis. The Erice ILD Working Group also proposed criteria for defining PPF. 16 These criteria shared several common elements. Firstly, the diagnosis must be an ILD other than IPF. This distinction is particularly important when considering the use of these criteria for the purpose of selecting populations for clinical trials. The ATS/ERS/JRS/ALAT clinical practice guideline underscores that PPF is not a diagnosis, but rather a manifestation of certain ILDs, and is agnostic to the underlying condition. 4 Secondly, evidence of fibrotic changes on high resolution computed tomography (HRCT) imaging must be present. These fibrotic features include coarse reticulation with traction bronchiectasis and honeycombing. INBUILD and the study of pirfenidone in unclassifiable ILD both required that participants have fibrotic changes on HRCT affecting at least 10% of lung volume at the time of enrollment. 12 15 Thirdly, evidence of progression of lung disease despite conventional treatment must exist. Each of these groups and trials had defined progression differently; however, with the 2022 ATS/ERS/JRS/ALAT clinical practice guideline, a consensus definition of PPF was determined and is shown in box 1 .

Identifying progressive pulmonary fibrosis 4

Interstitial lung disease diagnosis other than idiopathic pulmonary fibrosis

Radiologic evidence of pulmonary fibrosis

Evidence of progression, defined as meeting at least two of three criteria within the previous year with no alternative explanation:

Worsening respiratory symptoms

Absolute decline in FVC >5% predicted or absolute decline in DLCOc ≥10% predicted within one year of follow-up

Radiologic evidence of progression, including:

Increased extent or severity of traction bronchiectasis or bronchiolectasis

New ground glass opacity with traction bronchiectasis

New fine reticulation

Increased extent or coarseness of reticulations

New or increased honeycombing

Increased lobar volume loss

DLCOc=diffusing capacity of the lung for carbon monoxide corrected for hemoglobin; FVC=forced vital capacity

Progression of fibrosis may be more relevant than just its presence. A study that followed patients from the Scleroderma Lung Studies I and II for a median of eight years found that decline in forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) over two years was a better predictor of mortality than baseline FVC and DLCO. 17 However, progression can be determined only by serial testing, which may delay lung preserving therapy. Figure 1 shows a suggested algorithm for the evaluation and management of patients with suspected fibrosing ILD.

Epidemiology

Idiopathic pulmonary fibrosis.

IPF is the first or second most commonly encountered ILD in pulmonary practice and is estimated to account for 17-37% of all ILD diagnoses. 18 19 The incidence of IPF in the US and Europe is estimated to be 3-17 per 100 000 person years. 18 19 20 The lowest incidence rate of IPF globally is in Asia, with rates ranging from 1.2 to 4.6 per 100 000 per year. 21 In a study using Medicare data limited to people in the US aged 65 years and older, the incidence of IPF was as high as 93.7 per 100 000 person years and the prevalence was 494.5 cases per 100 000, reflecting age as the major risk factor for IPF. 22

Most common ILDs manifesting PPF

Rheumatoid arthritis is the most common autoimmune disease worldwide and is estimated to have a prevalence of 400-1000 cases per 100 000. 21 Clinically significant ILD occurs in 8-20% of patients with rheumatoid arthritis and is more common in men and those with greater overall disease severity. 21 23 The proportion of patients with RA-ILD who have progressive decline in lung function is estimated at 40%, on the basis of a study that found that 40% of patients with RA-ILD had a DLCO <40% predicted by five years after diagnosis of ILD. 24 The detection of a usual interstitial pneumonia (UIP) pattern on HRCT scan is associated with increased risk of both progressive lung disease and death, compared with a nonspecific interstitial pneumonia (NSIP) or organizing pneumonia pattern. 24 25

The prevalence of systemic sclerosis is estimated to be 7.2-33.9 cases per 100 000 in Europe and 13.5-44.3 cases per 100 000 in North America. 26 The proportion of people with systemic sclerosis who have SSc-ILD is as high as 90% on the basis of HRCT scanning. 27 Of patients with SSc-ILD, 18-25% have progressive worsening of lung function or HRCT findings. 10 28 29 30 Clinical features that predict progressive ILD include Black/African-American race, older age at disease onset, diffuse cutaneous skin disease, detection of antitopoisomerase antibodies, and lower baseline FVC and DLCO. 31 32 Histologic patterns of NSIP or UIP are not significantly associated with overall mortality in SSc-ILD. 33

Myositis related ILD

Idiopathic inflammatory myopathies are a group of rare systemic autoimmune disorders characterized by inflammation of skeletal muscle and sometimes skin, with a reported incidence of 0.2-0.9 cases per 100 000 person years. 34 The subtypes most commonly associated with ILD are dermatomyositis, polymyositis, and antisynthetase syndrome. 35 The reported prevalence of ILD in myositis ranges widely from 19.9% to 86%. 35 In a single center retrospective study, 31% of patients diagnosed as having myositis had ILD. 36 Of the patients with ILD, 33% had complete resolution of their lung disease with treatment and 16% had deterioration of their ILD after a median 34 months of follow-up. 36 An organizing pneumonia pattern on HRCT often responds to immunosuppressive therapy leading to clinical resolution of disease, whereas a UIP pattern is associated more often with progressive disease and clinical deterioration. 36 37 38 39

Chronic hypersensitivity pneumonitis

In a study using US administrative claims based data, the prevalence of hypersensitivity pneumonitis was estimated to be only 1.67-2.71 cases per 100 000, of which approximately 25% met criteria for fibrotic or chronic hypersensitivity pneumonitis. 40 However, in studies from cohorts of patients with ILD of new onset, a clinical diagnosis of hypersensitivity pneumonitis is made in 18-47% of patients. 41 42 43 Most patients with hypersensitivity pneumonitis who have fibrotic disease at baseline will have progressive disease. 8 44 45 Salisbury and colleagues found that compared with patients with IPF, those with cHP and honeycombing on HRCT had a greater decline in FVC and similar median survival. 8

Idiopathic NSIP

The estimated prevalence of iNSIP is 1-9 cases per 100 000. 46 In a retrospective cohort study of patients with fibrotic iNSIP, 13% had progression of radiologic findings on HRCT, 36% had radiologic improvement, and 23% had stable findings. 9 The prognosis of fibrotic iNSIP is generally better than that of IPF, with a five year survival rate ranging from 45% to 90%. 47 48 49

Sarcoidosis

In the US, the prevalence of sarcoidosis is 141.4 per 100 000 in people identifying as Black or African-American, 49.8 in those identifying as white, 21.7 in those identifying as Hispanic, and 18.9 in those identifying as Asian. 50 Fibrotic (stage IV) lung disease is estimated to occur in less than 20% of people with pulmonary sarcoidosis. 51 52 In a retrospective cohort study of patients with stage IV sarcoid, 24.8% had worse lung function after a mean 6.2 years of follow-up, whereas lung function was improved in 39.3% and stable in 35.9%. 53

Unclassifiable ILD

The proportion of patients with new onset ILD who are deemed to have unclassifiable ILD after multidisciplinary discussion was 10% in one single center retrospective study. 54 In this study, 52% of patients had significant progressive decline in lung function or death. Additionally, patients with unclassifiable ILD had longer survival rates compared with IPF and similar survival compared with other ILDs with progressive fibrosis. 54

Pathophysiology

Pulmonary fibrosis is increasingly recognized to begin with damage to the epithelium, possibly induced by environmental insults including cigarette smoke, viruses, environmental dusts (for example, silica or asbestos), or, perhaps, autoimmune injury ( fig 2 ). 55 56 In support of this hypothesis, some genetic mutations associated with pulmonary fibrosis involve genes that are exclusively expressed in the lung epithelium. These include a mutation in the promoter region of MUC5B that enhances its expression and mutations in SFTPC that lead to production of a misfolded protein. 57 58 59 Furthermore, genetic studies in mice localize the fibrotic effects of mutations in genes associated with pulmonary fibrosis that are expressed in all cells to the lung epithelium. Important examples include deficiency in genes that maintain telomere length and genes associated with the Hermansky-Pudlak syndrome. 60 61 62

Mechanisms and signals involved in the development of pulmonary fibrosis and therapeutic targets. During normal repair after lung injury, tissue resident alveolar macrophages interact with other cells in the alveolar epithelium to clear apoptotic cells, particulates, and pathogens without disrupting the normal gas exchanging functions of the alveolus. Alveolar type 2 (AT2) cells differentiate into alveolar type 1 (AT1) cells, passing through a transitional state characterized by expression of keratin-17, thereby restoring the normal alveolar epithelium. During disordered repair, recurring injuries to alveolar epithelium, by either environmental insults or antigen stimulation, cause AT1 cell death as well as aberrant activation of AT2 cells. The process of AT2 cells differentiating into AT1 cells is impaired in regions of lung fibrosis. Partially differentiated keratin-17 positive (KRT17+) epithelial cells accumulate, where they are associated with fibrosis. These KRT17+ cells produce large amounts of connective tissue growth factor (CTGF) and express αvβ6 integrin, which has been shown to activate latent transforming growth factor β (TGF-β), both of which promote differentiation of fibroblasts into myofibroblasts. The abnormally activated alveolar epithelial cells also contribute to fibroblast and myofibroblast proliferation through the production of platelet derived growth factor (PDGF), TGF-β, and CTGF. In response to this failed attempt at epithelial repair, circulating monocytes are recruited into the alveolar space and differentiate into profibrotic alveolar macrophages. These monocyte derived alveolar macrophages (Mo-AM) secrete PDGF and other growth factors that promote the activation and proliferation of fibroblasts as well as their differentiation into myofibroblasts. In a reciprocal positive feed-forward loop, fibroblasts secrete macrophage colony stimulating factor (M-CSF), which maintains alveolar macrophages at the site of injury. Myofibroblasts secrete excessive extracellular matrix (ECM) proteins, leading to stiffening of lung tissue. Myofibroblasts over time produce TGF-β in an autocrine manner and lose their need for macrophages in order to proliferate. The stiff matrix inhibits fibroblast apoptosis in another positive feed-forward loop that contributes to self-sustaining fibrosis. Recombinant human pentraxin (rhPTX)-2 has been proposed to inhibit the recruitment of alveolar macrophages to areas of fibrosis, which in turn inhibits myofibroblast activation. Nintedanib (NTB) likely inhibits fibroblasts by blocking PDGF signaling, among other profibrotic signaling pathways. The exact mechanisms by which pirfenidone (PFD) slows the progression of interstitial pulmonary fibrosis remain incompletely understood. Pamrevlumab (Pmab) is an anti-CTGF antibody that also likely inhibits fibroblasts

The advent of single cell RNA sequencing and its application to animal models of lung fibrosis and clinical samples from patients with pulmonary fibrosis have brought the multicellular nature of pulmonary fibrosis into focus. 63 64 65 66 67 68 Repair of the injured alveolar epithelium requires the asymmetric division followed by differentiation of alveolar type 2 cells into alveolar type 1 cells. 69 70 During the process of alveolar type 2 to type 1 cell differentiation, a transitional cell population characterized by expression of keratin-8 in mice and keratin-17 in humans forms. 68 71 72 73 These keratin-8 or keratin-17 positive epithelial cells are found at low concentrations in the normal mouse or human lung, but they increase during pulmonary fibrosis and are specifically localized to fibrotic lung regions in mice and humans. 64 65 68 71 72 74 These results suggest that normal epithelial repair is disrupted in regions of lung fibrosis. In response to this failed repair, circulating monocytes are recruited to the alveolar space where they rapidly differentiate into profibrotic monocyte derived alveolar macrophages. 62 75 76 77 These alveolar macrophages form reciprocal circuits with matrix fibroblasts in which fibroblasts secrete macrophage colony stimulating factor (M-CSF) to maintain alveolar macrophages at the site of injury and alveolar macrophages secrete platelet derived growth factor (PDGF) and other growth factors that drive the differentiation of fibroblasts into myofibroblasts, which excrete excessive matrix proteins. 66 78 In addition, alveolar epithelial injury induces the activation of latent transforming growth factor β (TGF-β) in the matrix. 79 TGF-β is a cytokine that modulates cellular differentiation, proliferation, and apoptosis, as well as extracellular matrix production. 80 It also maintains alveolar macrophages and activates myofibroblasts. 81 82 Over time, myofibroblasts lose their requirement for alveolar macrophages for proliferation and matrix secretion, in part through autocrine production and activation of TGF-β, 83 84 resulting in spatially restricted regions of progressive fibrosis. 78 This model of pulmonary fibrosis suggests a multimodal strategy for treatment. Such a strategy might include therapies to accelerate the differentiation of alveolar type 2 into alveolar type 1 cells through inhibition of the integrated stress response, 68 85 therapies that reduce the recruitment or prevent the maintenance of profibrotic monocyte derived alveolar macrophages in the alveolar space, 86 and therapies that target signaling through TGF-β, PDGF, and other growth factors in myofibroblasts (for example, nintedanib). 11

Management of IPF

Currently approved treatment.

The most recent ATS/ERS/JRS/ALAT clinical practice guideline on the treatment of IPF recommends only two drugs for the treatment of IPF—pirfenidone and nintedanib. 4 The 2015 ATS/ERS/JRS/ALAT guideline also included a conditional recommendation for antacid therapy, and therefore its evidence is also discussed here. 87 Table 1 lists the major clinical trials that examined the use of pirfenidone and nintedanib in the treatment of IPF and PPF.

Major randomized clinical trials evaluating the use of antifibrotic medications in the treatment of IPF and progressive pulmonary fibrosis (PPF)

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Pirfenidone

The US Food and Drug Administration (FDA) approved pirfenidone for the treatment of IPF in October 2014. The approval was based on data from three phase 3 clinical trials—CAPACITY I, CAPACITY II, and ASCEND. With pooled data from the CAPACITY I and II trials, primary endpoint analysis found that pirfenidone reduced the mean decline in FVC per cent predicted over 72 weeks compared with placebo (−8.5% v −11.0%; P=0.005). 88 The ASCEND trial found that pirfenidone led to a 47.9% reduction in the proportion of particpants who had an absolute decline of 10% or more in the FVC per cent predicted or who died after 52 weeks (16.5% v 31.8%; P<0.001). 89 Prespecified secondary analyses that pooled data with the two CAPACITY trials found that treatment with pirfenidone was associated with decreased all cause mortality (3.5% v 6.7%; P=0.01) and IPF specific mortality (1.1% v 3.5%; P=0.006), compared with placebo. 89 Separate post hoc analysis of pooled data from the CAPACITY and ASCEND trials also found that participants receiving pirfenidone had a lower risk of respiratory related hospital admissions (7% v 12%; P=0.001). 91 The exact mechanisms by which pirfenidone slows the progression of IPF are not known, although several have been proposed. 92

The US FDA also approved nintedanib for the treatment of IPF in October 2014. This was based on two INPULSIS phase 2 clinical trials, which both found that nintedanib reduced the annual rate of decline in FVC at week 52 compared with placebo. 11 In INPULSIS 1, the difference in annual rate of decline in FVC was 125.3 (95% confidence interval 77.7 to 172.8) mL/year (P<0.001); in INPULSIS 2, the difference was 93.7 (44.8 to 142.7) mL/year (P<0.001). In prespecified pooled analyses, no significant difference was seen between nintedanib and placebo groups in the time to first investigator reported acute exacerbation, death from any cause, or death from a respiratory cause. Nintedanib is a tyrosine kinase inhibitor that was originally developed as an anti-angiogenic cancer drug designed to bind and block platelet derived growth factor receptor (PDGFR), fibroblast growth factor receptor 1 (FGFR-1), and vascular endothelial growth factor receptor 2. 93 94 PDGF is made by alveolar macrophages in response to injury and inflammation and contributes to the proliferation, survival, and migration of myofibroblasts, which deposit extracellular matrix proteins in the interstitial space. 94 95 FGF/FGFR signaling also contributes to lung fibrosis, specifically through FGF-2 which induces fibroblast proliferation and collagen synthesis in lung fibroblasts and myofibroblasts. 96 97 Through its inhibition of growth factor signaling, nintedanib is thought to reduce the proliferation and migration of lung fibroblasts, the transdifferentiation of fibroblasts to myofibroblasts, and the deposition of extracellular matrix. 94

Antacid therapy

Abnormal gastroesophageal reflux is common in patients with IPF and is a known risk factor for aspiration and microaspiration. 98 Regular use of antiacid therapy, either with proton pump inhibitors or histamine-2 blockers, is believed to decrease the lung injury induced by microaspiration of acidic gastric juices. 99 Although the 2015 ATS/ERS/JRS/ALAT IPF treatment guidelines give a conditional recommendation for the use of antacid therapy, even in patients without symptoms of gastroesophageal reflux, the 2022 updated guideline makes a conditional recommendation against its use for the purpose of improving respiratory outcomes. 4 The TSANZ/LFA guidelines state that antacid therapy has unclear benefit and do not make a recommendation for or against its use. 101 When examining IPF patients in the placebo arms of RCTs, one study that used the IPFnet trials found that antacid use at baseline was associated with reduced decline in FVC 102 ; however, a more recent study using the CAPACITY and ASCEND trials found that antacid therapy did not improve outcomes and was associated with an increased risk of infection in patients with advanced lung disease. 103 Similarly, the WRAP-IPF trial, a phase II randomized, unblinded, controlled trial, found that laparoscopic antireflux surgery in patients with IPF and abnormal gastroesophageal reflux did not significantly reduce the decline in FVC over 48 weeks. 104 However, in a pilot randomized, placebo controlled trial of participants with IPF and a history of cough, omeprazole use was associated with a reduction in cough frequency of 39.1% (−66.0% to 9.3%), although it was not statistically significant owing to small sample size. 105

Non-drug management

The most recent guidelines from leading international societies of pulmonary medicine recommend long term oxygen therapy for IPF patients with resting hypoxemia, as well as referrals for pulmonary rehabilitation and lung transplant evaluation in appropriate patients. 101 106 107 The current recommendation for supplemental oxygen therapy in IPF is largely based on indirect evidence from two landmark RCTs in obstructive lung disease that showed a survival benefit with long term oxygen therapy in patients with resting hypoxemia (PaO 2 55-65 mm Hg). 108 109 Evidence to directly support the use of supplemental oxygen in people with IPF and resting or exertional hypoxemia is limited. A 2016 Cochrane review that included three RCTs found no evidence to support or refute the use of ambulatory or short burst oxygen in patients with ILD and exertional hypoxemia owing to the limited data 110 ; however, a subsequent systematic review that included studies examining the use of oxygen during exercise or exercise training found that ambulatory oxygen was associated with a consistent increase in exercise capacity. 111

Pulmonary rehabilitation is a comprehensive intervention that includes exercise training, education, and behavior change. 112 A Cochrane review that included five randomized or quasi-randomized controlled trials found that among people with ILD, and IPF specifically, significant improvements in exercise capacity, dyspnea, and quality of life were seen immediately after pulmonary rehabilitation, with the quality of evidence rated as low to moderate. 113 A subsequent meta-analysis of four RCTs found that, in patients with IPF, pulmonary rehabilitation had no detectable benefit at long term follow-up. 114 The current ATS/ERS/JRS/ALAT guidelines recommend that most patients with IPF be treated with pulmonary rehabilitation (weak recommendation, low quality of evidence). 106

Given the progressive natural history of IPF, with a median survival time of 3.8 years after diagnosis, 22 guidelines recommend that appropriate patients undergo lung transplantation and that discussion of transplantation should occur at the time of diagnosis or soon after. 101 106 107 In North America, the percentage of lung transplants performed in patients with IPF has been increasing over the past three decades, and from 2010 to 2018 IPF was the most common indication for lung transplantation. 115 Although post-transplant survival is worse for patients with IPF than for those with COPD and other matched non-IPF patients, 115 116 lung transplantation is associated with a 75% reduction in risk of death. 117 From 1992 to 2017 median survival time for patients with IPF was 5.2 years post-transplant, which increased to 7.3 years among those who survived at least one year post-transplant. 118

Therapies in the pipeline for treatment of IPF

Several drugs for the treatment of IPF—recombinant human pentraxin 2, pamrevlumab, treprostinil, and N-acetylcysteine—have recent phase 3 clinical trials. Table 2 lists these trials along with the data from the phase 2 and 3 trials that support the potential role of these drugs as treatment for IPF.

Recent active phase 3 clinical trials of treatments for idiopathic pulmonary fibrosis and phase 2/3 trials supporting their study

Recombinant human pentraxin 2 (rhPTX-2; PRM-151)

PRM-151 is a recombinant human pentraxin 2 protein (rhPTX-2). Pentraxin 2, also known as serum amyloid P, inhibits the recruitment of profibrotic monocyte derived alveolar macrophages to areas of fibrosis. 123 This is predicted to limit signaling by macrophages that drive matrix remodeling and myofibroblast activation. 63 75

The effect of rhPTX-2 was studied in a phase 2 double blind, randomized, placebo controlled trial of patients with mild to moderate IPF. 86 Concurrent therapy with pirfenidone or nintedanib was permitted. For the primary efficacy endpoint, the least squares mean change in FVC per cent predicted at week 28 in participants treated with rhPTX-2 was −2.5, compared with −4.8 in those given placebo (difference of 2.3, 90% confidence interval 1.1 to 3.5; P=0.001). An open label extension study found a persistent treatment effect in participants who continued taking rhPTX-2, with a decline in the FVC per cent predicted of −3.6% per year. 119 In participants who started taking rhPTX-2, FVC decline improved from −8.7 per cent predicted per year in weeks 0-28 (while taking placebo) to −0.9 per cent predicted per year in weeks 28-52. Thirteen (12%) of 111 participants had adverse events that led to discontinuation of rhPTX-2. Four participants had events that were considered by investigators to be related to rhPTX-2, including IPF exacerbation, tendinitis, dysgeusia, and cardiomyopathy. A phase 3 randomized, double blind, placebo controlled trial to study the efficacy and safety of rhPTX-2 began recruitment in March 2021, with an estimated study completion date in March 2023 ( NCT04552899 ).

Pamrevlumab

Pamrevlumab is an anti-connective tissue growth factor (CTGF) antibody under investigation for the treatment of IPF. CTGF is a mediator of tissue remodeling, acting downstream of TGF-β on connective tissue cells and functioning to stimulate fibroblast proliferation and the production of extracellular matrix. 124 125 CTGF is produced at high concentrations by airway and epithelial cells, as well as by activated fibroblasts in the lung tissue of patients with IPF. 64

The effect of pamrevlumab in patients with IPF was investigated in the phase 2 randomized, double blind, placebo controlled PRAISE trial. 120 Patients included had mild to moderate IPF and were not permitted to be on treatment with pirfenidone or nintedanib. Patients treated with pamrevlumab had a decline in FVC of 2.9 per cent predicted per year compared with 7.2 per cent predicted per year with placebo (difference of 4.3 (0.4 to 8.3) per cent predicted per year; P=0.033). The proportion of patients with disease progression, as defined by decline from baseline FVC per cent predicted ≥10% or death at week 48, was also reduced in the pamrevlumab group compared with the placebo group (10.0% v 31.4%; P=0.013). The frequency of adverse events was similar in the pamrevlumab and placebo groups, and the events were generally mild or moderate in severity and typical of participants’ underlying medical conditions. ZEPHYRUS 1 and 2 are ongoing phase 3 randomized, placebo controlled trials to further evaluate the use of pamrevlumab in patients with IPF and are estimated to complete in 2023 ( NCT03955146; NCT04419558 ).

Inhaled treprostinil

Treprostinil is a prostacyclin analog that is approved by the US FDA as an inhaled solution (Tyvaso) for treatment of pulmonary arterial hypertension and pulmonary hypertension associated with ILD. Inhaled treprostinil causes vasodilation of pulmonary and systemic arterial vascular beds and inhibits platelet aggregation. 126 It has also been shown to reduce collagen deposition in a bleomycin induced mouse model of pulmonary fibrosis, in part by inhibiting TGF-β1 induced expression of collagen mRNA and protein. 127

INCREASE was a randomized, double blind trial that examined the use of inhaled treprostinil in the treatment of pulmonary hypertension in people with ILD. 121 The trial met its primary efficacy endpoint in finding that the least squares mean difference between the inhaled treprostinil group and placebo group in the change from baseline six minute walk distance was 31.12 (16.85 to 45.39) m; P<0.001). Serious adverse events were similar in the inhaled treprostinil and placebo groups. Post hoc analysis found a difference in change in FVC per cent predicted of 1.8% (0.2% to 3.4%; P=0.028), favoring inhaled treprostinil over placebo, by week 16. 128 Notably, this study also found that the largest treatment effect occurred in patients with IPF. Based on these data, a phase 3 randomized, double blind, placebo controlled study began in April 2021 to evaluate the safety and efficacy of inhaled treprostinil in people with IPF, with change in FVC as the primary outcome measure ( NCT04708782).

N-acetylcysteine

N-acetylcysteine is a tripeptide precursor of glutathione that has antioxidant effects in the lung. 129 130 Three randomized, placebo controlled trials have examined the use of N-acetylcysteine monotherapy in the treatment of IPF. 131 132 133 The primary outcome in each of these studies was change in FVC, and none found a significant difference between N-acetylcysteine and placebo groups. Similarly, after the results of these three RCTs were pooled, no significant benefit on mortality, change in FVC, quality of life, or adverse outcomes was seen. 87 Two randomized, placebo controlled studies, including the PANORAMA study, then examined N-acetylcysteine in combination with pirfenidone in patients with IPF. 134 135 Although neither found a significant difference in the incidence of adverse events, both studies found a greater decline in FVC in patients receiving N-acetylcysteine; however, both were limited by small sample size.

However, a post hoc analysis of the PANTHER-IPF trial, which randomized participants with IPF to receive N-acetylcysteine monotherapy, combined prednisone, azathioprine, and N-acetylcysteine, or placebo, identified a subgroup of patients with the TOLLIP TT genotype in which N-acetylcysteine monotherapy was associated with a significant decrease in the composite endpoint of lung disease progression, hospital admission, transplantation, or death (hazard ratio 0.14, 95% confidence interval 0.02 to 0.83; P=0.03). 136 The TOLLIP CC genotype was associated with a non-significant increase in risk of the composite endpoint (hazard ratio 3.23, 0.79 to 13.16; P=0.10), which was significant in replication cohorts. Based on these data, the PRECISIONS trial is a phase 3 clinical trial comparing the effect of N-acetylcysteine plus standard care in patients with IPF who have the TOLLIP TT genotype ( NCT04300920 ).

Treatment of inflammatory ILDs

The currently accepted treatment for inflammatory ILDs, including CTD-ILD, cHP, iNSIP, and unclassifiable ILD, is immunosuppression. However, the only RCT data supporting this approach come from studies in patients with SSc-ILD. 137 138 139 Additionally, the only immunosuppressive drug that is approved by the FDA for the treatment of SSc-ILD is tocilizumab. FaSScinate, a phase 2/3 RCT, and focuSSced, a phase 3 RCT, were the basis for the FDA approval of tocilizumab for the treatment of SSc-ILD. 139 140 The focuSSced trial randomly assigned 210 people with diffuse cutaneous systemic sclerosis to receive tocilizumab or placebo. 139 People with severe ILD were excluded, and the cohort had a mean baseline FVC per cent predicted of 82% and evidence of SSc-ILD on HRCT in 65% of cases. Although the primary endpoint of change in the modified Rodman skin score was not met, on analysis of secondary outcomes participants who received tocilizumab had less decline in FVC per cent predicted than did those who received placebo (absolute difference in least square mean of 4.2%, 2.0% to 6.4%; P=0.0002).

Although cyclophosphamide and mycophenolate mofetil are not approved by the FDA for the treatment of SSc-ILD, their use is supported by the Scleroderma Lung Studies I and II. In the Scleroderma Lung Study I, which randomized 158 patients with SSc-ILD to receive cyclophosphamide or placebo, the mean absolute difference in adjusted FVC per cent predicted at 12 months was 2.53% (0.28% to 4.79%; P<0.03), favoring cyclophosphamide. 138 The Scleroderma Lung Study II subsequently randomized 126 patients with SSc-ILD to receive either cyclophosphamide or mycophenolate mofetil. 137 No significant difference was seen in the primary outcome of FVC per cent predicted at 24 months, but mycophenolate mofetil was associated with fewer toxicities and was better tolerated.

The evidence to support the use of immunotherapies such as steroids, mycophenolate mofetil, azathioprine, cyclophosphamide, tacrolimus, and rituximab for the treatment of other inflammatory ILDs is limited to observational studies and case series. Despite this, immunosuppression remains the standard of care for CTD-ILD and cHP and should be considered as first line therapy. The RECITAL trial is ongoing and has randomized patients with severe and/or progressive CTD-ILD to receive either cyclophosphamide (as standard of care) or rituximab as first line therapy and may further clarify the role of rituximab in CTD-ILD. 141

Despite the use of immunosuppressive treatment, high morbidity and mortality associated with these ILDs remain. Thus, a clear mandate exists for better treatment strategies that may be informed by understanding the progressive fibrosing phenotype and the role of antifibrotics in its treatment.

Treatment of PPF

Although the non-uniformity of the interstitial lung diseases that manifest PPF poses a challenge to designing and conducting clinical trials, several studies have established a role for antifibrotic therapy in PPF ( table 1 ). 10 12 15 90

Strong evidence supports the use of nintedanib for PPF. The SENSCIS trial was a phase 3 RCT that investigated the efficacy of nintedanib versus placebo in 576 people with SSc-ILD. 10 Enrollment did not require evidence of disease progression but included only people who had fibrosis affecting at least 10% of the lungs on baseline HRCT. The primary endpoint, annual rate of decline in FVC over 52 weeks, was lower in the nintedanib arm (difference 41.0 (2.9 to 69.0) mL/year). INBUILD, another phase 3 RCT of nintedanib versus placebo, expanded inclusion criteria to any non-IPF progressive fibrosing ILD. 12 Enrollment required meeting the study criteria for progressive fibrosis, based on FVC decline, or a combination of worsening FVC, symptoms, or imaging findings. The primary endpoint of annual rate of decline in FVC over 52 weeks was again lower in the nintedanib arm (difference 107 (65.4 to 148.5) mL/year). The difference was greater for the nearly two thirds of participants with a radiographic pattern of UIP (difference 128.2 (70.8 to 185.6) mL); however, a definitive treatment effect could not be inferred for other radiographic patterns of fibrosis.

Nearly half of the participants in the SENSCIS trial (48.5%) were concurrently taking mycophenolate mofetil, and subgroup analysis found no heterogeneity in nintedanib’s treatment effect according to baseline mycophenolate mofetil use. 10 142 Although the absolute reduction in FVC decline associated with nintedanib use was less in participants taking mycophenolate mofetil, the relative reduction in FVC decline was similar in those taking and those not taking mycophenolate mofetil (40% v 46%). Notably, participants receiving mycophenolate mofetil and placebo had a similar adjusted mean annual rate of FVC decline to those receiving nintedanib alone (−66.5 v −63.9 mL/year); however, the authors note that this comparison was out of the scope of the trial. The INBUILD trial excluded people who were receiving concomitant immunosuppression for ILD.

The data supporting pirfenidone in PPF are less robust. Pirfenidone was studied in two completed phase 2/2b RCTs. The first enrolled 253 people with unclassifiable ILD, including those with interstitial pneumonia with autoimmune features, and evidence of progressive loss of lung function. 15 The primary endpoint used home spirometry and provided unreliable results that could not be analyzed. The secondary outcome, using on-site spirometry, compared the mean decline in FVC over 24 weeks and showed a treatment difference favoring pirfenidone over placebo (difference 95.3 (35.9 to 154) mL; P=0.002). The RELIEF study enrolled only 127 of the planned 374 people with PPF, including those with CTD-ILD, cHP, iNSIP, and asbestos induced lung fibrosis. 90 The trial was terminated early owing to slow enrollment and for futility. The result was that 47% of participants, in both arms, had imputed data. Despite being underpowered by early termination, when imputed data were included, the primary endpoint of absolute change in FVC per cent predicted from baseline to 48 weeks was lower in participants taking pirfenidone (P=0.049). The median difference in change in FVC per cent predicted per year ranged from 1.69% to 3.53%, depending on the test used. The finding remained significant on multiple sensitivity analyses. Although the analysis of the primary outcome performed without imputation was not statistically significant, these findings may be clinically relevant. Clinical trials of both pirfenidone and nintedanib that are ongoing in a variety of PPF subsets are noted in table 3 .

Ongoing randomized clinical trials of antifibrotic drugs for treatment of idiopathic pulmonary fibrosis and progressive fibrosing interstitial lung disease

Gaps in knowledge in management of PPF

Identifying and treating ppf.

Recognition of a progressive fibrosing phenotype of ILD is important to both treatment strategies and prognosis. However, before May 2022, the diagnosis of PPF had been hampered by the lack of established clinical criteria and biomarkers. Additionally, the proposed criteria do not account for time from disease onset and may identify early inflammatory disease without a progressive fibrosing phenotype. Early decline in FVC in inflammatory ILDs may be remediated with immunosuppressive treatment, and a progressive fibrosing phenotype may never occur despite the proposed criteria being met early in the course of disease. Nevertheless, this needs to be balanced with the consideration that earlier treatment directed toward fibrosis may help to preserve lung function in patients who ultimately develop a progressive phenotype.

When immunosuppressive treatment is efficacious in inflammatory ILDs, it is continued. When an inflammatory ILD has progressive fibrosis despite immunosuppression, the question is whether to escalate immunosuppressive therapy or to start treatment with an antifibrotic drug such as nintedanib. Treatment decisions should consider the time from disease onset, as immunosuppressive therapies may be more likely to be effective early in the disease course. The prospective trials of immunosuppressive treatments for SSc-ILD recruited people early in the disease course and showed stabilization of lung function with cyclophosphamide, mycophenolate, or tociluzimab. 137 138 139 Acute and subacute cases of hypersensitivity pneumonitis may resolve with antigen avoidance with or without a short course of corticosteroids. However, once cHP develops and fibrotic features are present on imaging, five year mortality is similar to that of IPF at 50%. 8 In this setting, immunosuppressive therapy is unlikely to be beneficial and treatment with antifibrotics should be offered. Similarly, in CTD-ILD, antifibrotics should be strongly considered once progressive fibrosis has been established. Whether immunosuppression should continue when antifibrotic therapy is introduced also remains unclear. Although it is associated with worse outcomes in IPF, data in SSc-ILD from the SENSCIS trial suggest that treatment with combined immunosuppression and antifibrotic therapy may be advantageous. 10

Given the complex and multicellular pathobiology of pulmonary fibrosis, defining disease endotypes that can be identified by patterns of clinical characteristics, radiologic features, and biomarkers is important. These endotypes can then be used to guide initial therapy and to modify treatment over time. The recognition of PPF creates a further need to develop biomarkers of progressive disease. A comprehensive review of diagnostic and prognostic biomarkers was recently published. 143 Of the many studies examining biomarkers, most are observational and retrospective in design and few have been validated in separate prospective cohorts. For these reasons, biomarkers are infrequently used in clinical practice. 143 Single cell RNA sequencing and spatial transcriptomic studies conducted on explanted lungs obtained at the time of transplant when fibrosis is well established suggest relatively little heterogeneity between pulmonary fibrosis with differing initiating factors. 63 64 144 These findings suggest the need to obtain samples from patients with early disease to guide the selection of initial therapy and monitor the response to therapy over time.

The first large prospective study to evaluate biomarkers in IPF examined serum specimens from the PROFILE cohort, a longitudinal cohort of treatment-naive patients with IPF. 145 After measuring 123 serum proteins, the investigators focused on surfactant protein D (SFTPD), matrix metalloproteinase-7 (MMP7), CA19-9 (ST6GALNAC6), and CA-125 (MUC16). Including the discovery and validation phases of the trial, the study included 312 participants with IPF (145 with stable disease and 155 with progressive disease at follow-up) and 50 healthy controls. Although MMP7 was higher in patients with IPF compared with controls, it did not predict disease progression or mortality. SFTPD had higher discriminatory power for distinguishing IPF from healthy controls and identifying patients at high risk of progression. Although neither CA19-9 nor CA-125 could distinguish disease from controls, CA19-9 was most highly predictive of progressive fibrosis, and increasing concentrations of CA-125 predicted both disease progression and overall survival. As CA19-9 and CA-125 are relatively new markers in IPF, immunohistochemical localization of these markers was done in control and fibrotic lung tissue to ensure relevance to lung disease. CA19-9 and CA-125 were present in the apical bronchial epithelium in normal lungs, whereas in the fibrotic lung these markers were seen throughout the metaplastic epithelium in fibrotic lesions.

The largest study to examine biomarkers in non-IPF ILD is a retrospective study in 148 people with CTD-ILD, 98 with cHP, and 159 with unclassifiable ILD. 146 Six biomarkers of interest were evaluated with the primary endpoint of progression-free survival defined as survival without lung transplant or ≥10% decline in FVC over two years. The investigators found that increased serum concentrations of CXCL13 were associated with decreased survival in all three disease subgroups, but the optimal threshold concentration varied substantially between subgroups. CXCL13 is a chemokine that is chemotactic for B lymphocyte migration, and increased concentrations have been associated with ectopic germinal centers in autoimmune disease. 147 The authors speculate that the CXCL13 threshold variability may reflect different underlying biology, with inflammatory phenotypes of ILD having a higher baseline concentration overall, and therefore may indicate that CXCL13 could be useful in identifying a population of patients responsive to immunosuppression.

Genetic biomarkers may identify patients at increased risk for pulmonary fibrosis and predict disease progression. Patients with heterozygous mutations of either the TERT gene or the TERC gene, which are part of the telomerase complex genes, are at increased risk of IPF, as are those with shortened telomeres. 148 Although the use of telomere length testing in patients with suspected familial forms of idiopathic ILD varies in clinical practice, no formal recommendations on its use exist. A single nucleotide polymorphism (SNP) in the promotor region of the MUC5B gene (rs35705950) that increases the expression of the gene is associated with the development of IPF but has unclear effects on disease severity and survival. 149 150 Three SNPs in the TOLLIP gene have also been associated with IPF. 151 TOLLIP encodes toll interacting proteins that are linked to the lung’s immune responses, including modulation of TGF-β signaling. 152 Post hoc genotyping of TOLLIP and MUC5B was performed on previously collected samples from people enrolled in the PANTHER trial, 132 and identified polymorphisms within these genes were suggested to modify the effect of treatment with N-acetylcysteine or immunosuppression. 136 The results of this analysis were used to support further investigation of N-acetylcysteine in IPF patients with the TOLLIP rs3750920 TT genotype through the PRECISION trial ( NCT04300920 ).

Emerging therapies and diagnostics

Advanced diagnostics.

Newer methods that exploit advances in transcriptomics and proteomics may not only advance our understanding of the pathobiology of fibrosing lung diseases but may also serve to improve the utility of biomarkers. They offer a personalized approach to the management of PPF by eliciting the specific biologic pathways that are active at a given point in time and thereby might facilitate targeted therapy. Machine learning tools offer promise to iteratively improve the predictive power of these information-rich multi-omics data by incorporating detailed clinical and imaging metadata, including the response to therapy.

Currently available for clinical use, the Envisia Genomic Classifier (EGC) was developed using machine learning methods applied to exome enriched RNA sequencing data from whole lung biopsies (bulk RNA) in combination with histologically confirmed diagnoses. The product of this is an algorithm that differentiates UIP from non-UIP histologic patterns by recognizing the transcriptomic signature of UIP. This classifier was validated using an independent dataset in the BRAVE studies. 153 In these studies, samples were obtained from 84 people with suspected ILD undergoing planned, clinically indicated lung biopsy procedures. The transcriptome analysis showed that biopsy samples histologically classified as UIP were enriched for gene expression pathways associated with cellular metabolism, adhesion, and developmental processes. However, samples histologically classified as non-UIP showed gene expression pathways associated with immune activities, lipid metabolism, stress response, and cell death. Using the developed algorithm and a single transbronchial lung biopsy sample to distinguish UIP from non-UIP histologic patterns, the EGC had a sensitivity of 63% (95% confidence interval 51% to 74%) and a specificity of 86% (71% to 95%). If three to five samples were used, the sensitivity improved to 74% (51% to 90%) and specificity improved to 93% (68% to 100%). The EGC has now been validated in an additional study using the BRAVE cohort, which found that it had a negative predictive value of 60.3% (46.6% to 73.0%) and a positive predictive value of 92.1% (78.6% to 98.3%) for histology proven UIP. 154

The EGC identifies a transcriptomic pattern associated with histologic UIP in patients with indeterminant radiographic patterns. This does not equate to a diagnosis of IPF. Rather, the results from EGC are an additional piece of data that can be incorporated into a multidisciplinary discussion to achieve a consensus diagnosis. The ECG has also not yet been studied in PPF. However, future studies to evaluate the use of transcriptomic tools to identify or predict progressive fibrosis and predict response to antifibrotics in this patient population may be instrumental in developing precise therapeutic targets.

Bulk RNA sequencing like that used in the EGC provides an average measure of gene expression across the heterogenous cell populations that make up the lung. This creates a problem of averaging in which a change in cellular composition (for example, an increased number of inflammatory cells) can drive changes in average gene expression and biologically important signals in cell populations or subpopulations can be missed. Single cell RNA sequencing avoids these problems by measuring gene expression within each individual cell, allowing one to compare cell populations—for example, alveolar type 2 cells—in health and disease. In addition to identifying biomarkers, single cell RNA sequencing allows one to generate hypotheses about which cellular interactions drive fibrosis and can be targeted pharmacologically. Although still too costly and time consuming for clinical practice, single cell RNA sequencing has become an invaluable discovery tool, particularly when applied to small samples from patients with early disease, including those obtained by bronchoscopic lavage or biopsy.

Along with improved tools for exploring the pathobiology of IPF and PPF, several national and international ILD registries are enrolling people. Registries differ from clinical trials in that they are large, they allow for prolonged follow-up time, and enrollment is inclusive and thus more reflective of the general population of patients with a given disease. Participants should be well characterized as to important clinical features of their disease. Insights derived from registries complement clinical trials and may answer questions about the long term effectiveness of treatments. Current registries will need to be expanded to accommodate digitized images and genomic data that will facilitate the training of multimodal machine learning classifiers to predict disease endotypes and responsiveness to therapy.

Resolution of fibrosis

IPF and PPF are characterized by self-sustaining fibrosis and progressive decline in lung function. The therapies approved and undergoing phase 3 clinical trials for the treatment of IPF and PPF have been shown only to slow decline in lung function, and none has shown resolution of fibrosis. However, growing evidence suggests that fibrosis may be reversible, particularly with removal of the underlying cause of injury. 155 A recent review covered the biology of self-sustaining fibrosis and emphasized three processes necessary for resolution of fibrosis—elimination of matrix producing cells, clearance of excess matrix, and regeneration of normal tissue constituents. 5

Metformin has been found to ameliorate pulmonary fibrosis in bleomycin induced mouse models of lung fibrosis. 156 157 Metformin inhibits mitochondrial complex I to activate adenosine monophosphate activated protein kinase (AMPK), which subsequently inhibits TGF-β. 157 158 159 160 Metformin is able to normalize myofibroblast sensitivity to apoptosis and stimulate turnover of collagen via AMPK dependent activation of autophagy. 156 By eliminating matrix producing myofibroblasts and promoting the clearance of excess matrix, metformin, or other AMPK activators, may be able to reverse established fibrosis. Notably, however, when patients who were randomized to placebo in the CAPACITY and ASCEND trials of pirfenidone were stratified by baseline metformin use, no significant difference in disease progression associated with metformin use was seen. 161 One potential reason for the discrepancy between these findings and experimental studies may be the high doses (65-300 mg/kg) of metformin and intraperitoneal route used in the mouse models. 156 157

The resolution of fibrosis requires not only breaking the positive feed-forward loops that sustain and amplify fibrosis but also regenerating normal tissue to occupy the area of former fibrosis. Alveolar type 2 cells are a partially committed stem cell population in the adult lung that undergo asymmetric division and differentiation to replace damaged alveolar type 1 cells 69 74 162 ; however, when alveolar type 2 cells are isolated from IPF lung tissue they have impaired regenerative ability compared with healthy tissue. 163 In single cell RNA sequencing data from lung explants from patients with pulmonary fibrosis, investigators have noted the emergence of a population of epithelial cells characterized by expression of low concentrations of keratin-5 and increased levels of keratin-17. 64 65 These cells also express high levels of genes associated with senescence, including p16 ( CDKN2A ), p21 ( CDKN1A ), and plasminogen activator inhibitor 1 ( SERPINE1 ), among others. A transcriptionally similar population of cells has been observed in murine models of pulmonary fibrosis and in a murine model of alveolar regeneration after pneumonectomy. 68 71 72 73 In all of these studies, these cells are characterized by increased expression of keratin-8, along with similar senescence associated genes. All three initial reports of these cells showed them to be a transitional cell population that forms during the differentiation of alveolar type 2 to type 1 cells. 68 71 72 Strunz and colleagues showed that, during bleomycin induced fibrosis, these cells develop a transcriptomic signature suggestive of activation of the integrated stress response during their differentiation. 68 This is of interest because inhibitors of the integrated stress response have been shown to reduce fibrosis in animal models. 164 Watanabe and colleagues followed up on these results, showing that a small molecule inhibitor of the integrated stress response, ISRIB, accelerated the differentiation of alveolar type 2 cells into alveolar type 1 cells during fibrosis, reducing the number of keratin-8 positive cells. 85 This suggests that a decline in the function of the proteostasis network, as occurs during aging in model organisms, might impair the differentiation of alveolar type 2 cells, predisposing to the development of fibrosis. 165 Future studies are needed to determine whether the emergence of keratin-17 cells explains some of the increase in senescence markers observed in lung fibrosis. 166

Table 4 summarizes the most recent guidelines from the leading international societies on the management of idiopathic pulmonary fibrosis and highlights some of the key commonalities and differences between the recommendations. The ATS/ERS/JRS/ALAT clinical practice guidelines published in 2011 were updated in 2015 and 2022. 4 87 106 The JRS published a separate clinical practice guideline in 2018, which provided additional recommendations not previously included in the 2015 joint guidelines. 167 Specifically, for patients experiencing an acute exacerbation of IPF, they recommend against the use of polymyxin B (weak recommendation, low quality of evidence), neutrophil elastase inhibitors (weak recommendation, very low quality of evidence), and recombinant thrombomodulin (weak recommendation, low quality of evidence) and recommend the use of immunosuppressant drug therapy (weak recommendation, low quality of evidence).

Comparison of guideline recommendations from ATS/ERS/JRS/ALAT, JRS, NICE, and TSANZ/LFA for treatment of idiopathic pulmonary fibrosis

NICE guidelines on the diagnosis and management of IPF were published in 2013 and last updated in 2017. 107 168 169 As seen in table 4 , NICE guidelines have minor differences from the ATS/ERS/JRS/ALAT guidelines, which may reflect the fact the NICE Guideline Development Group is required to make decisions based on the best available evidence of both clinical effectiveness and cost effectiveness. 170 The TSANZ and the LFA published a position statement on the treatment of IPF in 2017, which differs from the ATS/ERS/JRS/ALAT guidelines in its recommendation to use disease severity to guide decisions on antifibrotic therapy and its neutral stance on antacid therapy. 101

The first international gudelines on the treatment of PPF came in May 2022 with the ATS/ERS/JRS/ALAT clinical practice guideline. 4 This guideline suggested nintedanib for the treatment of PPF in patients who have not responded to standard management for non-IPF fibrotic ILD (conditional recommendation, low quality evidence). The committee made no recommendation for or against the use of pirfenidone for the treatment of PPF and recommended further research into the use of pirfenidone in non-IPF ILDs.

Tremendous advances have been made in elucidating the biologic processes that promote and sustain pulmonary fibrosis. The recognition that ILDs other than IPF may also have a progressive fibrosing phenotype has also been instrumental in moving forward the treatment options for patients with PPF and conceptualizing how to best manage these patients in the future. Importantly, nintedanib has been shown to slow progression of disease in patients with PPF, and several ongoing clinical trials are examining whether pirfenidone may also be beneficial. Several promising therapies are in the pipeline that may offer novel ways of treating IPF that could potentially be used instead of or in addition to the currently available antifibrotics. However, significant gaps in knowledge surrounding the treatment of IPF and PPF remain. Notably, we lack biomarkers and other diagnostic tests that can be used early in the disease course (before functional decline is present) to determine when patients with PPF may benefit from antifibrotics. Additionally, more studies are necessary to examine whether antifibrotics should be used in lieu of or in addition to immunosuppression when no extrapulmonary indications for immunosuppressive therapy are present. The essential question of whether and how established fibrotic disease can actually be reversed and normal lung tissue and function restored also remains. Future research must consider these questions to continue advancing the care for patients with these devasting diseases.

Glossary of abbreviations

ALAT—Latin American Thoracic Association

AMPK—adenosine monophosphate activated protein kinase

ATS—American Thoracic Society

cHP—chronic hypersensitivity pneumonitis

CTD-ILD—connective tissue disease associated ILD

CTGF—connective tissue growth factor

DLCO—diffusing capacity for carbon monoxide

EGC—Envisia Genomic Classifier

ERS—European Respiratory Society

FDA—Food and Drug Administration

FGFR-1—fibroblast growth factor receptor 1

FVC—forced vital capacity

HRCT—high resolution computed tomography

ILD—interstitial lung disease

iNSIP—idiopathic nonspecific interstitial pneumonia

IPF—idiopathic pulmonary fibrosis

JRS—Japanese Respiratory Society

LFA—Lung Foundation of Australia

M-CSF—macrophage colony stimulating factor

MMP7—matrix metalloproteinase-7

NICE—National Institute for Health and Care Excellence

NSIP—nonspecific interstitial pneumonia

PDGF—platelet derived growth factor

PDGFR—platelet derived growth factor receptor

PF-ILD—progressive fibrosing interstitial lung disease

PPF—progressive pulmonary fibrosis

RA-ILD—rheumatoid arthritis associated ILD

RCTs—randomized controlled trials

rhPTX-2—recombinant human pentraxin 2

SFTPD—surfactant protein D

SNP—single nucleotide polymorphism

SSc-ILD—systemic sclerosis associated ILD

TGF-β—transforming growth factor β

TSANZ—Thoracic Society of Australia and New Zealand

UIP—usual interstitial pneumonia

Research questions

What drives progressive pulmonary fibrosis in patients with interstitial lung disease (ILD)?

Do biomarkers exist that can predict which patients with ILD will develop progressive pulmonary fibrosis before they have lung function decline?

What is the optimal timing for starting antifibrotics in patients with non-idiopathic pulmonary fibrosis fibrotic? Should antifibrotics be started only after patients have shown progression on immunosuppression?

Should immunosuppression be continued in patients with progressive pulmonary fibrosis who start treatment with antifibrotics?

Do therapies exist that can reverse or resolve pulmonary fibrosis?

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

Contributors: All authors contributed to the intellectual content, did the literature search, and participated in the preparation, editing, and critical review of the manuscript.

Funding: GYL is supported by NIH grant F32-HL162318 and North Western University’s Lung Sciences Training Program 5T32HL076139-17. GRSB is supported by supported by NIH grants ES013995, HL071643, and AG049665 and the Veterans Administration grant BX000201.

Competing interests: We have read and understood the BMJ policy on declaration of interests and declare: none.

Patient involvement: No patients or members of the public were involved in the design, conduct, reporting, or dissemination plans of this manuscript.

Provenance and peer review: Commissioned; externally peer reviewed.

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Air pollution exposure—the (in)visible risk factor for respiratory diseases

• Review Article
• Open access
• Published: 04 March 2021
• Volume 28 , pages 19615–19628, ( 2021 )

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• Gabriel-Petrică Bălă   ORCID: orcid.org/0000-0002-1877-1327 1 ,
• Ruxandra-Mioara Râjnoveanu 2 ,
• Emanuela Tudorache 1 ,
• Radu Motișan 3 &
• Cristian Oancea   ORCID: orcid.org/0000-0003-2083-0581 1  

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There is increasing interest in understanding the role of air pollution as one of the greatest threats to human health worldwide. Nine of 10 individuals breathe air with polluted compounds that have a great impact on lung tissue. The nature of the relationship is complex, and new or updated data are constantly being reported in the literature. The goal of our review was to summarize the most important air pollutants and their impact on the main respiratory diseases (chronic obstructive pulmonary disease, asthma, lung cancer, idiopathic pulmonary fibrosis, respiratory infections, bronchiectasis, tuberculosis) to reduce both short- and the long-term exposure consequences. We considered the most important air pollutants, including sulfur dioxide, nitrogen dioxide, carbon monoxide, volatile organic compounds, ozone, particulate matter and biomass smoke, and observed their impact on pulmonary pathologies. We focused on respiratory pathologies, because air pollution potentiates the increase in respiratory diseases, and the evidence that air pollutants have a detrimental effect is growing. It is imperative to constantly improve policy initiatives on air quality in both high- and low-income countries.

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Introduction

Air pollution represents one of the biggest risk factors for human health. It is an invisible killer that hides around us, influencing both young and old generations. According to the World Health Organization (WHO), each year, 7 million people die due to air pollution. The most affected pathologies are chronic obstructive pulmonary disease, lung cancer, and respiratory infections, including pneumonia, stroke, and heart disease. Nine out of 10 individuals breathe air with polluted compounds, which penetrate deep into the lung tissue, and furthermore in the cardiovascular system (Ghebreyesus 2018 ) (World Health Organization 2018 ) (Tiotiu et al. 2020 ).

The most exposed individuals are elderly persons, infants, pregnant women, and persons with comorbidities (Mannucci et al. 2015 ). An estimated 43% of lung diseases and 24% of strokes are attributed to air pollution.

We performed an electronic search on PubMed for literature published in the last 5 years, with the last search date on February 15, 2020. The following terms were used: “air pollution,” “particulate matter,” “biomass,” “smoke,” “sulfur dioxide,” “nitrogen dioxide,” “carbon monoxide,” “ozone,” “chronic obstructive pulmonary disease,” “asthma,” “lung cancer,” “idiopathic pulmonary fibrosis,” “respiratory infections,” “bronchiectasis,” and “tuberculosis.” The terms were also searched in combination, such as “particulate matter and lung cancer” and “air pollution and chronic obstructive pulmonary disease.” The results were restricted to full-text studies of humans and mechanisms via animal experiments. Systematic reviews, meta-analyses, reviews, and publications from the WHO were included in the search. We additionally included older references if they had an important impact on the subject area, according to our knowledge.

General air pollution

Air pollutants are classified into two main categories: primary air pollutants (pollutants emitted directly into the atmosphere) and secondary air pollutants (pollutants that are formed within the atmosphere itself) (World Health Organization 2005 ) (Mannucci et al. 2015 ).

Primary air pollutants are those released from a direct source, such as exhaust pipes from a mobile vehicle, or from a stationary source, such as factory chimneys. At the same time, contaminated dust can also be distributed by the wind to uncontaminated areas. These pollutants can be calculated by measuring the amounts emitted by the source itself. Primary air pollutants are represented by oxides of nitrogen, carbon monoxide (CO), sulfur dioxide (SO 2 ), volatile organic compounds (VOCs), and carbonaceous and non-carbonaceous primary particles. The International Agency for Research on Cancer (IARC) has classified emissions from burning coal in an indoor environment as potentially carcinogenic to humans. These were observed with sufficient evidence in both animals and humans (Barone-Adesi et al. 2012 ).

There are many sources of primary air pollutants, but the most significant are road traffic and power plants. Additionally, industrial and residential heating based on wood, coal. or oil contributes to increasing the degree of air pollution (World Health Organization 2005 ) (Guarnieri and Balmes 2014 ) (Kravchenko and Lyerly 2018 ) (Minichilli et al. 2019 ).

Secondary air pollutants are formed through chemical reactions in the atmosphere, with natural components such as water and oxygen. Secondary air pollutants include ozone (O 3 ), oxides of nitrogen, and particulate matter (PM) (World Health Organization 2005 ) (Guarnieri and Balmes 2014 ) (Mannucci et al. 2015 )

The chemical composition of air pollutants is diverse and depends on the source. Additionally, a seasonal pattern is observed, with higher average daily concentration levels of nitrogen dioxide (NO 2 ), CO, PM10, and fine particulate matter (PM2.5) during the cold season, while O 3 concentration levels tended to be higher during the warm season (Bernardini et al. 2019 )

Air pollutants released by coal-fired power plants have raised concerns about their impact on public health. PM2.5 can have both short-term and long-term consequences on human health. In a study conducted by Cheng-Kuan Lin et al., a strong association was observed between the increase in coal capacity per person and an increase in the relative risk for lung cancer, both in men and women. These were observed by a factor of 85% among women and 59% among men. Based on these data, it is predicted that in 2025, a total of 1.37 million cases of lung cancer will be correlated with coal-fired power plants (Lin et al. 2019 ).

Outdoor (ambient) air pollutants

Sulfur dioxide.

Sulfur dioxide (SO 2 ) and PM come from the process of burning fossil fuels and represent the essential components of air pollution. Sulfurous and sulfuric acids are formed as a result of the oxidation process of SO 2 . Natural sources include volcanoes, but significant concerns have been encountered in large metropolitan regions where coal is being used for domestic heating or for poorly controlled combustion for industrial installations (World Health Organization 2005 ).

Exacerbation of respiratory symptoms has been shown to be related to exposure to SO 2 emitted by coal-burning power plants, and lower concentrations were associated with respiratory deaths. The major anthropogenic sources of SO 2 are found in developing countries and come from burning fossil fuels that contain sulfur. The reason for burning fossil fuels is due to heating homes, use in power plants, and powering vehicles (Kravchenko and Lyerly 2018 ). Sulfur dioxide concentrations are lower since indoor concentrations are absorbed by walls, furniture, and inhalation systems (World Health Organization 2005 ).

Nitrogen dioxide

There are many species of nitrogen oxides, but the one with the most important effect on human health is NO 2 . NO 2 is a gas with a brown color, having a distinctive powerful scent. Nitric oxide spontaneously produces dioxide when it is exposed to air. It is a powerful oxidant that produces nitric acid and nitric oxide by reacting with water, and it is an important trace gas affecting human health. It absorbs solar radiation, contributing to low visibility in the atmosphere and plays a direct role in global climate change.

NO 2 undergoes further transformations, and after the photochemical reaction sequence is initiated by its solar radiation-induced activation, newly generated pollutants are created, containing organic, nitrate, and sulfate particles, all measured at PM2.5 and PM10. Among natural sources, the represented sources include lightning, inclusion of stratospheric nitrogen oxides, and bacterial and volcanic actions. The major anthropogenic sources are mobile sources (combustion engines) and stationary combustion sources (power generation sources) (World Health Organization 2005 ) (Kravchenko and Lyerly 2018 )

Patients with asthma and chronic obstructive pulmonary disease (COPD) have been associated with an increased risk of respiratory hospitalization after exposure to NO 2 (Kravchenko and Lyerly 2018 ). In addition, exposure to air pollution due to traffic vehicles increases the risk of developing bronchiolitis obliterans post-lung transplant syndrome (Johannson et al. 2015 ).

In China, a systematic review and meta-analysis by Sun et al. identified a positive correlation between short-term ambient exposure to NO 2 and pulmonary diseases. A 10-μg/m 3 increase in NO 2 concentration was associated with an increase of 1.4% in mortality due to respiratory disease and 1.0% in hospital admission. Elderly individuals had an even higher susceptibility (Sun et al. 2017 ).

Carbon monoxide

The most important source of environmental CO is incomplete combustion of traffic-related fossil fuels, leading to >50% of emissions in urban areas, other sources (such as manufacturing and natural processes, etc.) being less prominent (World Health Organization 2005 ).

Carbon monoxide is considered to be a “silent killer” due to its toxicity arising from its ability to bind hemoglobin more strongly than oxygen, increasing the risk of asphyxia-related deaths at high levels of exposure or hypoxic tissue damage at low levels of exposure (World Health Organization 2005 ).

Asthma, bronchiectasis, and pneumonia have been associated with ambient short-term exposure to CO (Zhao et al. 2019 ). The study of Zhao et al. conducted over 4 and 1/2 years, with a daily mean ambient CO of 0.88 mg/m 3 , varying from 0.40 to 3.13 mg/m 3 , reported an increased risk for daily outpatient visits for respiratory disease, with a higher effect on women and elderly patients (Zhao et al. 2019 ).

In different studies, a positive association between daily exposure to PM2.5, SO 2 , and CO and an increased risk of mortality from respiratory diseases and lung cancer was reported. For a 1-mg/m 3 increase in CO and a 10-μg/m 3 increase in PM10, there has been a 1.9% and 4.8% increase in total deaths, respectively (Xue et al. 2018 ) (Table 1 ).

Volatile organic compounds

Volatile organic compounds (VOCs) are compounds with a high vapor pressure of one or more carbon atoms, which will lead to their release in the atmosphere (Ciganek and Neca 2008 ). Compounds from the atmosphere, in a state of a vapor phase, such as oxygenates, hydrocarbons, halogenates, and other carbon compounds, are the main components of VOCs (World Health Organization 2005 ).

There are different sources of VOCs. They can arise from natural causes, such as forest fires, vegetation, and animals, but also from artificial causes, such as vehicles. Natural sources of VOCs represent a higher percentage, but anthropogenic sources contribute significantly to reducing air quality.

The most important sources of VOCs are released by industrial and agricultural sources. At the same time, handling solvents or solvent-based products contributes significantly to VOC concentrations. Samples that were collected from road dust or soil were based on volatile organic compounds, such as benzene, toluene, styrene, ethylbenzene, and xylene, as well as aliphatic hydrocarbons (mostly n -alkanes), dichloromethane, and disulfide carbon (Ciganek and Neca 2008 ).

Oxidative stress and decreased lung function are related to exposure to low levels of VOCs. Additionally, airway inflammation could be related to exposure to increased levels of VOCs in everyday life (Kwon et al. 2018 ).

In a national cross-sectional representative survey that was conducted by the Indoor Air Quality Observatory, N -undecane and 1,2,4-trimethylbenzene were correlated with asthma in 8.6% of cases, while trichloroethylene, ethylbenzene, and m/p- and o-xylene were associated with rhinitis (Billionnet et al. 2011 ).

In a French cross-sectional study on farmers, indoor mean VOC concentrations were smaller in workplaces than in dwellings. Working in a rural environment involves a degree of exposure to various risk factors such as agricultural machinery and fires, exposure to capricious weather, agricultural land working, and exposure to various organic compounds. Following this study, individuals mentioned that respiratory symptoms, such as dyspnea, cough, sneezing, and wheezing, were the most common. They were present in 44% of people when manipulating plants that had been harvested. Asthma and early airway obstruction were linked with exposure to VOCs and PM and in farmers (Maesano et al. 2019 ).

Ozone (O 3 ) is a chemical compound that is not directly emitted into the air but is formed through a series of complex reactions. Atomic oxygen and nitric oxide are formed after NO 2 splits. Atomic oxygen later combines with oxygen-forming ozone. Ozone is disintegrated by reacting with nitric oxide, resulting in NO 2 and oxygen. Ambient concentrations depend on several factors: the concentration of NO 2 and VOCs, sunshine intensity, atmospheric convection, and the proportion of VOCs to nitrogen oxides (World Health Organization 2005 ) (Guarnieri and Balmes 2014 ).

Daily concentrations of air pollutants are higher in the cool seasons than in the warm seasons, except for O 3 , which is higher during warm seasons (Wang et al. 2019d ). Ground-level ozone (O 3 ) is considered one of the most dangerous air pollutants in the USA and the European Union, being a strong oxidizing compound. In recent years, O 3 levels have remained high without showing any decline and will remain a constant public health problem, especially with the progression of global warming (Guarnieri and Balmes 2014 ) (Wang et al. 2019c ).

Concentrations of O 3 can increase during late spring and summer months due to photochemical reactions, along with its precursors, such as VOCs. High concentrations of O 3 can be associated with various local and long-range transports of anthropogenic emissions. In winter, lower photochemical processes result in a smaller contribution of this factor to PM2.5 mass (18%) (Bari and Kindzierski 2017 ). Human exposure to ozone is correlated with a high risk of respiratory disorders, such as asthma exacerbation and lung inflammation, loss of lung function, and cystic fibrosis (Johannson et al. 2014 ). Additionally, it has been shown to interact with cerebral blood vessels by modulating the expression of genes involved in brain vasoreactivity, irritating mucous membranes, altering the levels of serotonin, and affecting the immune system (Bernardini et al. 2019 ).

• Particulate matter

According to the World Health Organization (WHO), the standard for daily PM2.5 concentration is 25 μg/m 3 , while the annual average is 10 μg/m 3 . Approximately 92% of the world’s population lives in locations where the mean PM2.5 mass concentration surpasses this amount. Approximately 3 million persons die from outdoor air pollution each year (Wang et al. 2019b ).

Particulate matter (PM) is represented by a complex mixture containing components with diverse physical and chemical characteristics. The potential for these particles to cause injury varies due to their chemical composition and source. Additionally, their size and physical characteristics represent major concerns for public health (World Health Organization 2005 ).

Particles are classified in general by their aerodynamic diameter. PM can generally be classified into three major fractions: coarse particles, exceeding 2.5 μm in aerodynamic diameter; fine particles, which are smaller than 2.5 μm; and ultrafine particles, which are smaller than 0.1 μm (100 nm). PM10 contains PM2.5 and thoracic coarse mass (the distinction between PM10 and PM2.5 is generally presented as coarse mass). In general, PM10 mass contains 40–90% of the PM2.5, the rest being considered coarse PM (World Health Organization 2005 ) (Guarnieri and Balmes 2014 ) (Mannucci et al. 2015 ).

PM with a 2.5–10-μm aerodynamic diameter, also known as coarse PM, is stored particularly in the head and in the upper respiratory tract. PM2.5 is usually stored in the deep respiratory airways, primarily in the small airways and alveoli, while ultrafine PM (<0.1μm) is stored in the alveoli (World Health Organization 2005 ) (Guarnieri and Balmes 2014 ) (Liang et al. 2019 ).

PM2.5 are primarily formed from gases. These particles usually emerge as ultrafine particles created by the formation of very small particles (nuclei) by condensation-nucleation of low vapor pressure substances generated by chemical reaction into the atmosphere or by high-temperature vaporization (World Health Organization 2005 ) (Mannucci et al. 2015 ) (Kravchenko and Lyerly 2018 ). The principal precursor gases are represented by nitrogen oxides, ammonia, SO 2 , and VOCs. At the same time, fluctuations in the concentrations of these compounds may alter ambient PM concentrations. On the days when PM10 concentration exceeds 50 μg/m 3 PM, nitrate becomes the main compound of PM10 and PM2.5 (World Health Organization 2005 )(Kravchenko and Lyerly 2018 ).

There are numerous sources of both human activity and natural source-related particles. Specific sources impact different regions of the world, but more than two-thirds of PM 2.5 is due to industrialization in developed areas.

The origin of PM2.5 is variable. It can come from several sources, such as vehicle traffic, followed by dust generation, aerosols from regional transport, agricultural activities, and the burning of biomass for cooking or heating. It is difficult to appreciate the contribution of each source and to further recognize the PM formation mechanism (Zhang and Cao 2015 ).

Photochemical conversion of secondary pollutants (SO 4 2− , NO 3 − , and NH4+) represents 3.7% of PM2.5 and 2.4% of PM10 (Lee et al. 2018 ). Concentrations of NH 4 + , NO 3 − , and SO 4 2− on days with higher pollution can be two to four times higher than on unpolluted days ( p < 0.01), according to the study of Pan et al, where PM2.5 samples were gathered from two metropolitan areas (Beijing and Shanghai) on polluted and unpolluted days in the fall of 2017 (Pan et al. 2019 ). Additionally, seasonal variations in PM2.5 have been described in different regions of the world.

In a Canadian study conducted by Md. Aynul Bari from May 2009 to December 2015, the overall mean and median concentrations of PM2.5 were comparatively higher in winter than in summer (Bari and Kindzierski 2017 ). The same observation was reported in the Chinese study of Yan-Lin Zhang et al., with remarkable seasonal variability in PM2.5, which was highest during winter and lowest during summer. On the other hand, increased levels of PM2.5 are also found in the spring and autumn due to the contribution of dust particles and the start of burning biomass. In addition, the lowest and highest PM2.5 concentrations frequently occur in the afternoon and evening hours (Johannson et al. 2014 ).

An investigation of the origin of wintertime high PM2.5 pollution days revealed that in addition to traffic emissions, another significant source that helped increase PM2.5 in winter was a mixed factor represented by local industry and agriculture (deduced as gas emission sources and upstream oil) (Bari and Kindzierski 2017 ).

Indoor air pollutants

Biomass smoke.

Biomass smoke is a major public health problem (Balcan et al. 2016 ). Coal and biomass fuels are used by almost 3 billion people worldwide. A large part of the world’s population still depends on solid fuel for cooking, firewood, and charcoal (Nsoh et al. 2019 ). Individuals generally use different types of fuels for heating and cooking, such as “smoky coal” (bituminous), “smokeless coal” (anthracite), and wood (Barone-Adesi et al. 2012 ).

Compounds emitted from smoky coal combustion are present in abundance, such as polycyclic aromatic hydrocarbons (PAHs), methylated PAHs, and heterocyclic aromatic compounds containing nitrogen. Following an incomplete combustion process, solid fuel releases a significant amount of toxic particles. These will then be inhaled and cause multiple respiratory symptoms. Symptoms may include upper respiratory tract conditions, such as cough, nasal obstruction, vocal dysfunction, rhinorrhea, laryngeal spasm, and lower respiratory tract symptoms, such as dyspnea, wheezing, and cough (Nsoh et al. 2019 ).

Approximately half of the world’s population cooks and heats using unprocessed biomass fuels and coal. Several diseases are associated with exposure to solid fuel smoke, including lung cancer, chronic obstructive pulmonary disease, and respiratory infections (Barone-Adesi et al. 2012 ). In the study by Barone-Ades et al., it was observed that mortality due to lung cancer was higher in people who used smoked charcoal than in those who used no-smoke charcoal throughout their lives. In the study, 9962 people used smokeless coal, and 27,310 used smoked coal. The absolute risk of death from lung cancer in individuals who used smoked charcoal was higher for women (20%) than men (18%). As a comparison, the percentage of people who used smokeless charcoal and developed lung cancer was only 0.5%. These values are similar to those observed in heavy smokers in Western countries, with a value between 20 and 26% (Barone-Adesi et al. 2012 ).

Lung function begins to deteriorate after exposure to smoke for more than 15 years. The chance of having modified pulmonary function increases as the duration of exposure increases. In rural areas, women are generally more exposed due to their conventional lifestyle. In a case-control study, from a total of 115 women exposed to biomass smoke, 23.8% had small airway disease, 19.1% had obstruction, and 17.3% had a restriction pattern on pulmonary function tests (Balcan et al. 2016 ).

Public health focus on respiratory disease

• Chronic obstructive pulmonary disease

COPD is a multifactorial condition characterized by chronic airway obstruction that is incompletely reversible, progressive, and associated with an abnormal inflammatory response of the lung to harmful particles or gases (Singh et al. 2019 ).

Ambient air pollution is associated with COPD morbidity and mortality. From systemic analyses, it was observed that morbidity from COPD is correlated with a short-term increase in air pollution (Adar et al. 2014 )(Zhang et al. 2016 ) (Tian et al. 2018 ).

The body’s response may differ from person to person. The ability of each person to react to air pollution may differ in the Chinese population compared with the North American or European population due to differences in air pollution concentration and the composition of the polluted air. At the same time, the pre-existing pathology of one population may be different from another. In a study conducted in Beijing, China, a reduction in the average concentration of PM2.5 up to 58 μg/m 3 was observed in 2017 compared with 2013 when the average concentration was 87 μg/m 3 . Although a significant reduction was observed, the value was still high, given that the reference value was 10 μg/m 3 according to the WHO. However, it was observed that there were 161,613 hospitalizations for exacerbations of COPD (most patients were men over 65 years of age). Short-term exposure to air pollutants was correlated with hospital visits in the COPD emergency sections, resulting in subsequent hospitalizations and mortality (Liang et al. 2019 ).

In a population-based study involving 3941 nonsmoking Taiwanese adults, 791 had COPD. Exposure to PM2.5 at concentrations higher than 38.98 μg/m 3 was associated with increased predisposition to COPD among nonsmokers in Taiwan. However, exposures to concentrations of 32.07–38.98 μg/m 3 and 29.38–32.07 μg/m 3 were not significant (Huang et al. 2019 ).

From the multitude of studies that have shown a link between COPD and air pollution, we selected this study.

At high concentrations, air pollutants have a direct inflammatory effect on airway neuroreceptors and the epithelium. In addition, oxidative stress has been associated with pollutant exposure (O 3 , NO 2 , PM2.5) (Johannson et al. 2014 ). Airway inflammation can be induced by specific pollutants (O 3 , NO 2 , PM2.5), while airway hyperresponsiveness can be induced by O 3 and NO 2 (Johannson et al. 2014 ) (Kravchenko and Lyerly 2018 ).

The EGEA study conducted on 204 adult asthmatic patients revealed important data about the role of oxidative stress in the association between air pollution and asthma. The levels of fluorescent oxidation products (FlOPs), an oxidative stress-related biomarker, increased with PM10 and O 3 , and the risk of persistent asthma increased with plasma FlOP levels (Havet et al. 2019 ).

Air pollution represents one of the most important factors aggravating asthma in children, with higher incidences in European and Caribbean regions (Cadelis et al. 2014 )(Akpinar-Elci et al. 2015 ). One of the contributing factors is Saharan dust (Gyan et al. 2005 ). Saharan particles are composed of mineral origins. They are composed of a multitude of particles, such as clay, quartz, silicon oxide, and carbonates. They are lined with organic matter represented by bacteria and spores or pollen grains. Saharan dust contains PM10 and PM2.5–10, which can further predispose to an increase in visits to the emergency service for patients aged 5–15 years (Cadelis et al. 2014 ).

In a retrospective study of 5 years conducted by Muge Akpinar-Elci, the relationship between Saharan dust and exposure, climatic variables, and asthma was analyzed. There were 4411 recorded asthma-related emergency visits, and variation in asthma was correlated with dust concentration (Akpinar-Elci et al. 2015 ). Additionally, in a study conducted by Cadelis et al., there were 836 visits for asthma, with 514 boys and 322 girls (Cadelis et al. 2014 ).

In a study that took place in 10 European cities, the incidence of asthma among children was 14%, and after exposure to air with polluting compounds from road traffic, children with exacerbated asthma constituted 15% of the cohort. Asthma symptoms have been correlated with short-term exposure to ambient PM2.5 and PM10 in prospective cohorts, particularly in children with allergic sensitivity (Guarnieri and Balmes 2014 ). In a cohort study conducted by Bowatte et al., exposure to traffic-related air pollution (TRAP) was associated with both persistent and new-onset asthma in adults. Living < 200 m from a major road was correlated with greater odds of new asthma for middle-aged persons who never had asthma by 45 years. Asthmatic participants at 45 years had an increased risk of persistent asthma up to 53 years if they were living < 200 m from a major road compared with asthmatic participants living > 200 m from a major road (Bowatte et al. 2018 ).

• Lung cancer

Lung cancer represents one of the most common types of cancer and has a poor prognosis. The most important risk factor incriminated in developing lung cancer is active smoking, but exposure to environmental occupational carcinogens, residential radon, and passive smoke is also recognized as risk factors (Raaschou-Nielsen et al. 2013 ).

Although the association between lung cancer and long-term exposure to air pollution has been clarified, the link between lung cancer mortality and short-term exposure to air pollution remains unknown. The number of lung cancer cases is expected to increase due to continuous exposure to air pollution in regard to massive industrialization, an aging population and constant high smoking prevalence (Wang et al. 2019d ). PM2.5, PM10, and O 3 contribute to oxidative stress within the respiratory system and therefore potentially facilitate pulmonary inflammation and could initiate or promote the mechanisms of carcinogenesis (Xing et al. 2019 ). PM2.5 is considered the most relevant pollutant (Hamra et al. 2014 ).

In 2010, cancers of the trachea, bronchial tree, or lungs attributable to exposure to PM2.5 accounted for approximately 7% of total mortality. The mechanisms that have been incriminated in the association between PM2.5 and lung cancer include DNA deterioration and cell cycle changes (Longhin et al. 2013 ). PM2.5 was also related to increased production of reactive oxidative species.

A correlation was observed between the aerodynamic diameter of the fine particles in the medium ≤ 2.5 (PM2.5) and the incidence and mortality from lung cancer. Based on a meta-analysis of 18 studies, the correlation between PM2.5 and PM10 and the incidence and mortality of lung cancer were studied. Following the analysis, it was observed that the meta-relative risk was 1.09 for lung cancer related to PM2.5 and 1.09 for PM10. Additionally, the risk of adenocarcinoma associated with PM 10 was 1.29, while for PM2.5, it was 1.4. These results can help us better analyze the pathology of bronchopulmonary cancer in connection with air pollution (Hamra et al. 2014 ).

In the Ahsmong-2 study, it was shown that for each 10 μg/m 3 increase in ambient PM2.5, the incidence of lung cancer increased, although the individuals from the study were exposed to low levels of ambient PM2.5 and had never smoked. The percentage was higher for individuals who had a longer period of residence and who had spent more than 1 h/day outside. The predominant type of cancer was adenocarcinomas, with a percentage of 66.4% (Gharibvand et al. 2017 ).

Wang et al. suggested that the carcinogenic effects of PM2.5 vary by gender as well as by the environment in which individuals live, i.e., rural or urban. It has also been observed that younger people have a lower sensitivity than elderly people. For individuals in rural areas, it was observed that with a growth level of the average concentration of PM2.5 by 10 μg/m 3 , the incidence and mortality from lung cancer were 15% and 23% among men, compared with 22% and 24% among women, respectively. Thus, following this study, the results showed that women have a meaningful risk of developing lung cancer in correlation to PM2.5 exposure (Wang et al. 2019a ).

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, and limited to the lungs. It is a progressive lung disease with a complex etiology (Johannson et al. 2018 ) characterized by progressive worsening of dyspnea and lung function and is associated with poor prognosis (Raghu et al. 2011 ).

There are not enough studies to certify the effects of air pollution on interstitial lung disease. However, in a study conducted by Johansson, it was shown that acute exacerbations of IPF were associated with an increase in the mean level, the maximum level, and the number of exceedances above accepted standards of O 3 and NO 2 (Johannson et al. 2014 ). Of the six criteria regulated by the US Environmental Protection Agency, particulate matter (PM), ground level (O 3 ), and NO 2 were strongly related to adverse respiratory effects (Johannson et al. 2015 ).

One potential mechanism by which ambient air pollution may cause interstitial lung disease is oxidative stress through the generation of excess reactive oxygen species (ROS), such as radical hydroxide and superoxide anion. IPF patients exhibit evidence of reduced antioxidant capacity, suggesting that they may have an increased vulnerability to excess ROS (Johannson et al. 2015 ). Another explanation for the progressive evolution of the disease was highlighted by the study of Winterbottom et al. on 135 subjects evaluated between 2007 and 2013. The results showed a strong association between PM10 levels and a decrease in forced vital capacity (FVC). With each μg/m 3 increase in PM10, there was an additional 46 cc/year decline in FVC. The significant relationship observed between the exposure to coarse (PM10) and the decline rate of FVC was not reported for PM2.5, showing an inverse relationship between the diameter size of the particle and penetration into the airways. Each 5 μg/m 3 increase in ambient PM2.5 concentration at residences corresponded with an additional 1.15 L/year increase in oxygen use on the 6-min walking test (6MWT) (Winterbottom et al. 2018 ). The results are equivocal, because the study conducted by Kerri A. Johannson et al. showed that PM10, PM2.5, and NO2 were associated with reduced lung function, but the changes were independent of air pollution exposure (Johannson et al. 2018 ).

There were no significant relationships between mean weekly change in air pollutant levels and concurrent weekly changes in forced vital capacity (FVC), forced expiratory volume during the first second (FEV1), University of California San Diego Shortness of Breath Questionnaire (UCSD-SOBQ), or visual analog scale (VAS) scores. Nevertheless, regarding the duration or interval of assessment periods, there was no significant association between the mean level of air pollutants and subsequent changes in lung function. Additionally, neither higher cumulative mean exposures nor maximal exposures to air pollution were associated with a more rapid decline in FVC or FEV1 over the study period. However, in patients with IPF, average exposures to NO 2 , PM2.5, and PM10 were associated with lower FVC, indicating that air pollution may influence the severity of disease in some individuals (Johannson et al. 2018 ).

In a study with 436 patients performed by Johannson et al., 75 of them had at least one acute exacerbation, and a subgroup of 13 patients had more than one exacerbation. During the exposure period, acute exacerbation of IPF was correlated significantly with increased mean rates, maximum levels, and amounts of O 3 and NO 2 exceedances. Increased exposure to O 3 and NO 2 over the preceding 6 weeks was associated with a high risk of acute exacerbation of IPF. This suggests that air pollution could be correlated with the development of this clinically significant event. At the same time, there were no consistent relationships between PM10, SO 2 , or CO and acute exacerbation of IPF compared with NO 2 , O 3 , and PM2.5 (Johannson et al. 2014 ).

Respiratory infections

In the cross-sectional study of Nsoh et al., 1849 patients diagnosed from January 2013 to April 2016 with acute respiratory infections (ARIs) were registered. Of the selected patients, more than 70% used at least one form of solid fuel for cooking. In poorly ventilated homes, the impact of this exposure was irritation of the respiratory tract and eyes and an increased risk of cancers related to long-term inhalation of this poor-quality air. The probability of developing ARI was 3.62 times higher for people who were exposed to cooking indoors than for those who were not exposed. Additionally, the chances of developing ARI were 1.91 times higher for those exposed to open fire than for those who were not exposed. Thus, PM2.5 values were 13.2 times higher than what the WHO recommends. Dry weather and dust also increase the risk of developing ARI (Nsoh et al. 2019 ).

A study conducted in China found that with increasing concentrations of PM2.5 and PM2.5–10 compounds, the number of hospital visits for upper airway infections and pneumonia meaningfully increased. The increase in the average concentration, which accumulated over 6 days, was 10 μg/m 3 (Z. Zhang et al. 2019 ).

Zheng P et al. constructed a seasonal model of cases of respiratory infections, revealing a higher preponderance in the period with lower temperatures. While children aged 5–14 years had a higher chance of developing acute respiratory infections (55.1%), those under 5 years had a higher chance (60.5%) of developing lower acute respiratory infections. The concentrations of air pollutants PM10, NO 2 , and SO 2 exhibited lower values in the warmer period. Young children have a higher degree of susceptibility than older individuals due to their less developed immune system, tighter airways, higher frequency of respiration, and higher long-term exposure to air pollutants of the lower respiratory tract. Due to the excessive use of coal for heating during the colder season, winds also contribute to increased concentrations of air pollutants (P. Zheng et al. 2017 ).

Bronchiectasis

Bronchiectasis is defined as inappropriate and permanent dilatation of the bronchi. It is a chronic respiratory disease, with many patients having frequent exacerbations. Due to their exacerbations, lung function will subsequently decrease, furthermore, increasing mortality (Garcia-Olivé et al. 2018 ).

Infectious pathogens are often incriminated in the majority of bronchiectasis exacerbations, but frequently, no pathogen can be identified. In a study conducted by C. Pieter Goeminne et al. on 432 patients diagnosed through high-resolution computed tomography (HRCT) and clinically confirmed bronchiectasis, for a 10 μg/m 3 increase in PM10 and NO 2 , the chance of developing an exacerbation in that same day increased by 4.5% and 3.2%. In total, 11.2% for PM10 and 4.7% for NO 2 were the risk of having an exacerbation for a 10-μg/m 3 increase in the concentration of air pollutants. Subanalysis showed considerably higher relative risks through spring and summer due to increased expected outdoor air pollution exposure (Goeminne et al. 2018 ).

Additionally, in a retrospective observational study conducted in Badalona, SO 2 was considerably related to an increase in the hospitalization number (Garcia-Olivé et al. 2018 ). Through our search of the literature, we noticed that there are few studies on the connection between air pollution and bronchiectasis.

Tuberculosis

According to the WHO, in the 2019 Global Tuberculosis Report, approximately 10 million people worldwide fell ill with tuberculosis in 2018, and it is the leading cause of a single infectious agent. Worldwide, tuberculosis is considered to be the 10th leading cause of death (WHO-Global Tuberculosis Report 2019 n.d. ) Tuberculosis (TB) is a disease whose prevalence has been associated with socioeconomic risk factors that has a stronger association with urban settings, where there is greater exposure to air pollution (Jassal et al. 2012 ).

There is a direct correlation between air quality and tuberculosis incidence. Precipitation, atmospheric pressure, and relative humidity affect the incidence of tuberculosis by indirectly reducing the quantity of inhalable PM and SO 2 concentrations. On the other hand, wind plays a major role by increasing the incidence of tuberculosis by spreading pathogens (Zhang and Zhang 2019 ). Fine particulate matter and traffic-related air pollution might be associated with an increased risk of developing tuberculosis. This association is not due to direct exposure but rather to the impairment of the individual’s immunity (Lai et al. 2016 ). Popovic et al. showed in a systematic review that the pollutant most frequently associated with tuberculosis is PM2.5 (Popovic et al. 2019 ).

The Chengdu study also documented that exposure to ambient PM10, NO 2 , and SO 2 was linked to increased tuberculosis morbidity in China, but the lag time was 28 days for PM10 and 5 days for SO 2 and NO 2 , which can only be attributed to short-term effects (Zhu et al. 2018 ). Another study conducted by Lai et al. highlighted that an increased risk of active tuberculosis is related to exposure to fine particulate matter PM2.5. Furthermore, traffic-related air pollution, including nitrogen dioxide, nitrogen, and carbon monoxide, was associated with tuberculosis risk. On the other hand, PM10 was not linked with active tuberculosis, and O 3 was inversely associated with the risk of TB (Lai et al. 2016 ).

Similar to the last results, O 3 levels could not be significantly correlated with acid fast bacilli (AFB)-positive smears in the retrospective study of Jamal et al. Medical records of 196 individuals diagnosed with TB positivity at Los Angeles County and University of Southern California Medical Center Hospital were analyzed. A total of 111 had smear positivity, while 85 had smear negativity. There was a significant correlation in single pollutant models analyzing PM2.5 levels and smear-positive TB (Jassal et al. 2012 ).

The link between PM2.5 concentration, notably a 10 μg/m 3 increase in PM2.5 levels, and active TB was also noted in a study conducted from 2014 to 2017 in Lianyungang. For the single-pollutant model, the association between a 10-μg/m 3 increase in PM10 concentration and SO 2 concentration and active TB was significant. Additionally, a potential correlation between relatively long-term outdoor exposure to PM2.5, PM10, SO 2 , and NO 2 and active TB was observed in the time-series study conducted in the northeastern region of Jiangsu Province, China. In the multipollutant models, ambient PM10 and NO 2 remained significant, and the association was not altered in subgroups of different genders or ages (Li et al. 2019 ).

In addition, exposure to pollution over different periods of time may be associated with drug resistance. Exposure to PM2.5, PM10, O 3 , and CO has been associated with drug-resistant TB, including first-line monodrug resistance, polydrug resistance, and multidrug resistance (MDR), in both single- and multiregression models. In the retrospective study of Yao et al., conducted in Jinan city, China, from January 1, 2014 to December 31, 2015, 752 new culture-confirmed TB cases reported in TB prevention and control institutions of Jinan were included. The results showed significant monodrug resistance, and polydrug resistance increased the risk for ambient PM2.5, PM10, O 3 , and CO exposure. The most significant association for PM2.5 was noticed at 540 days of exposure, for O 3 was noticed at 180 days of exposure, and for PM10 and CO, it was noted from 90 to 540 days of exposure. Of the 752 cases, 18.8% were first-line drug-resistant cases with streptomycin having the highest rate of resistance (15.3%), 13% were second-line resistant, fluoroquinolones having the highest rate of resistance (11.3%), 12.3% were resistant to more than 1 drug but not MDR, and 3.3% were MDR-TB (Yao et al. 2019 ).

NO 2 nitrogen dioxide, SO 2 sulfur dioxide, PM2.5 particulate matter with diameter < 2.5μm in diameter, PM10 particulate matter with diameter < 10μm in diameter, O 3 ozone, CO carbon monoxide, COPD chronic obstructive pulmonary disease, IPF idiopathic pulmonary fibrosis

Animal experiments

Animal experiments have opened up new perspectives on air pollution (Edwards et al. 2020 ). Air pollution contributes to increased inflammation. When polluted air is inhaled, its first stop is the lungs. This is where oxidation-reduction first occurs (Gangwar et al. 2020 ). Oxidative stress arises from altering the balance between oxidants and antioxidants. Altering this balance will increase oxidative stress and cause the increase of lung pathologies through promoting inflammation of the airways. PM consists of a number of components capable of generating ROS, which subsequently increase inflammatory mediators in the lungs (Valavanidis et al. 2013 ).

In a study conducted by Edward et al., it was observed that rats exposed to TRAP, compared with those not exposed, exhibited increased gene expression changes related to oxidative stress, inflammation, aging, and fibrosis in the heart (Edwards et al. 2020 ). While Zheng et al. showed that following exposure to tracheal diesel particles, mice presented an increase in transient oxidative stress in the lungs, Sun et al. showed that PM2.5 accentuates the degree of atherosclerosis, degrades vasomotor tone, and determines vascular inflammation in mice that have been chronically exposed to low concentrations of PM2.5 (Q. Sun et al. 2015 ) (X. Zheng et al. 2019 ) (Gangwar et al. 2020 ). Rats that were exposed to ozone showed 8-hydroxy-2′-deoxyguanosine (8-OHdG) and heme oxygenase-1 (HO-1) in macrophages, developing rigid lungs with reduced function (Sunil et al. 2013 ) (Valavanidis et al. 2013 ).

Fibrosis and reversible cardiac dysfunction were observed in mice after intratracheal exposure to PM2.5 (Gangwar et al. 2020 ). Oxidative stress in the myocardium is increased in those exposed to ultrafine particles (Cozzi et al. 2021 ). Qin and all demonstrated that after intratracheal exposure to PM2.5, the most sensitive were the extremes of age compared with adult animals, developing heart dysfunction and reversible fibrosis (Qin et al. 2018 ) (Gangwar et al. 2020 ). Cozzi et al. showed that myocardial damage in mice exposed to ultrafine particles is double that in those not exposed (Cozzi et al. 2021 ).

General information

When the level of pollution is high, informing the population should be a priority. This information should be free and easy to access so that outdoor activity is reduced during periods with higher air pollution (Tiotiu et al. 2020 ).

Air quality alerts are beneficial to the population. The population is notified when air quality alerts occur (Wen et al. 2009 ). In a study conducted by Graff and Neidell, it was found that when the population was alerted by smog alerts, outdoor physical activity on visits to the Griffith Park Observatory and Los Angeles Zoo decreased by 8% and 15%, respectively. However, when alerts were repeated on days 2 and 3, people did not take into account the smog alerts, with values of 0% and 5%, respectively (Graff and Neidell 2009 ). These warnings should be repeated as often as possible and should be of particular interest for patients with cardiopulmonary pathology, as well as healthy patients who may subsequently develop chronic diseases (Wen et al. 2009 ).

From a real estate point of view, both large cities and those with fewer inhabitants should be channeled on development so that the degree of pollution does not affect the quality of life of the population. This should be done from the beginning and not developed later, after the urbanization plan has been made. This would help reduce air pollution from the start. Public institutions, as well as the community, must contribute to reducing the degree of pollution. However, although institutions should play a key role in reducing pollution, it can also be reduced by individual freewill (Carlsten et al. 2020 ).

As medical staff inform asthmatics to avoid aeroallergens, patients with chronic cardiopulmonary disease should also be informed by the degree of air pollution and how it may affect their health. Otherwise, they may develop new symptoms or experience worsening of pre-existing symptoms. The air quality index (AQI) should be consulted frequently by patients to cancel outdoor activities when air quality is poor (Shofer et al. 2007 ) (Wen et al. 2009 ).

The use of masks helps reduce the degree of inhalation of noxious substances. However, not all masks are equally effective, and this depends on both the type of mask and the filter it has (Carlsten et al. 2020 ). In a study conducted by Shakya et al., masks made from material were beneficial to a low degree in protecting particles with a diameter of 2.5 μm, while surgical masks were more effective. The most efficient in eliminating most tested particles was N95 masks. The material masks have a higher comfort but are much weaker than N95 masks (Shakya et al. 2016 ).

Conclusions

Today, although we know the impact of pollution on the respiratory system, we have tried to describe up-to-date information on how pollution affects the respiratory system and the pathologies associated with it (Fig. 1 ). This depends on the type of pollutant, its concentration in the environment, and its size. Air pollution potentiates the increase in respiratory pathology. It is important to constantly measure the quality of the air, both in developed and less-developed countries to ensure continued improvement.

NO 2− nitrogen dioxide, SO 2 sulfur dioxide, VOCs volatile organic compounds, CO carbon monoxide, PM2.5 particulate matter with diameter < 2.5 μm in diameter, PM10 particulate matter with diameter < 10 μm in diameter

Strength of this review

The characteristics of this review refer in particular to the lung diseases caused by air pollutants. The lung is one of the main human organs that have direct contact with the air and is able to filter inhalable pollutants. Lung damage by any other pathology corroborated with inhalable pollutants can later affect other organs and the whole body. For this reason, we considered it of major importance to classify the air pollutants and to present how each pollutant influences lung pathologies and can later affect the whole body.

Abbreviations

World Health Organization

sulfur dioxide

nitrogen dioxide

carbon monoxide

volatile organic compounds

International Agency for Research on Cancer

particulate matter

particulate matter with diameter < 2.5 μm in diameter

particulate matter with diameter < 10 μm in diameter

chronic obstructive pulmonary disease

fluorescent oxidation products

traffic-related air pollution

idiopathic pulmonary fibrosis

reactive oxygen species

forced vital capacity

6-min walking test

forced expiratory volume during the first second

University of California San Diego Shortness of Breath Questionnaire

visual analog scale

acute respiratory infections

high-resolution computed tomography

tuberculosis

multiresistance drug resistance

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Bălă, GP., Râjnoveanu, RM., Tudorache, E. et al. Air pollution exposure—the (in)visible risk factor for respiratory diseases. Environ Sci Pollut Res 28 , 19615–19628 (2021). https://doi.org/10.1007/s11356-021-13208-x

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BU Researchers See Future Where Lung Disease Is Treatable, and Damaged Lungs Are Regenerated

Figuring out how to make damaged lungs like new again has been Darrell Kotton’s life work. Now, he is one step closer

Darrell Kotton and his team imagine a future where they can use a patient’s own cells to fix lung damage caused by disease by reprogramming cells in a laboratory dish and transplanting them back into the patient. Photo by Jackie Niam/iStock

Jessica Colarossi

For more than 20 years, a team of Boston University scientists have been on a quest to not just figure out how to treat incurable lung diseases, but also how to regenerate damaged lungs so they’re as good as new.

That is the goal of pulmonologist Darrell Kotton and his lab at the Center for Regenerative Medicine (CReM), a joint effort between the University and Boston Medical Center, BU’s primary teaching hospital. By refining their work using sophisticated stem cell technology, Kotton and his team are closer to realizing that vision than ever before.

In two new studies published in Cell Stem Cell , BU researchers detail how they engineered lung stem cells and successfully transplanted them into injured lungs of mice. Two lines of cells targeted two different parts of the lung: the airways, including the trachea and bronchial tubes, and the alveoli, the delicate air sacs that deliver oxygen to the bloodstream. Their findings could eventually lead to new ways for treating lung diseases, including severe cases of COVID-19, emphysema, pulmonary fibrosis, and cystic fibrosis, a disease caused by a genetic mutation.

“We’ve accomplished this by getting better and better at generating the cells,” says Kotton, a BU Chobanian & Avedisian School of Medicine professor of medicine, director of CReM, and corresponding author on both papers.

Kotton and his team imagine a future where they can use a patient’s own cells to fix lung damage caused by disease by reprogramming cells in a laboratory dish and transplanting them back into the patient. The new lung cells would replicate, like regular cells do, replacing the damaged and diseased areas of the lung.

New Treatment Possibilities

Bringing damaged lungs back to normal function without a lung transplant is possible with stem cells , which can develop into other specialized cells in the body. There are many different types of stem cells that have been discovered over the years, but Kotton and his lab focus on a type called pluripotent stem cells .

These cells are found only in embryos. But in 2006 scientist Shinya Yamanaka figured out how to genetically reprogram adult skin or blood cells into an embryonic stem cell–like state. Those engineered cells are called induced pluripotent stem (iPS) cells, and won Yamanaka the Nobel Prize in Physiology or Medicine in 2012. Induced pluripotent stem cells can be turned into any cell type in the body, including lung cells. Kotton and his team—which includes Chobanian & Avedisian School of Medicine Professors Finn Hawkins and Xaralabos Varelas , College of Arts & Sciences Professor of Physics Pankaj Mehta , and many other researchers—developed methods for engineering each of the lung’s stem cells in the laboratory using iPS cells, including by using machine learning methods. This step helped them determine the best conditions for generating cells that could go on to be lung cells. And then they developed methods for transplanting them into experimental mouse models with injured lungs.

“We demonstrated that engineered cells, which have never before been part of a lung, can be transplanted into injured mouse lungs, where they integrate into the host’s respiratory system and behave similar to the host’s pulmonary cells,” says Michael Herriges, a postdoctoral fellow in the Kotton Lab and lead author of the paper focused on the lung air sacs . As one can imagine, making lung cells that can be used for therapy from just microscopic clumps of unspecified iPS cells is a long and complicated process—and one that has been Kotton’s life work.

“The fact that we can generate a functional engineered version in living tissue is still amazing to me and it opens up the possibility for new treatments for patients with lung disease,” Herriges says.

The fact that we can generate a functional engineered version in living tissue is still amazing to me and it opens up the possibility for new treatments for patients with lung disease. Michael Herriges

The cells that were transplanted into the mice lasted the entirety of their lifespan, over two years. Now, they must figure out whether or not the cells can actually prevent disease progression in the mouse models, and eventually they will have to test their technique in larger animals with lungs that more closely resemble human lungs.

“Many lung diseases are characterized by irreversible tissue damage,” says Martin Ma, an MD/PhD student in molecular and translational medicine and the lead author of the paper focused on lung airways . “Since the lung is not the most regenerative compared to other organs in the body, damage can lead to much suffering for patients without a ton of treatment options.”

Ma believes that years down the line, the process for fixing damaged lungs could appeal to patients who would rather not take medications every day for their whole lives, and at the least put another option on the table for patients who suffer from genetic lung diseases that do not have a current medical therapy. For example, a patient with a genetic lung disease like cystic fibrosis would have a drop of their blood taken. The blood cells would be reprogrammed into iPS cells, and then manipulated using methods developed in the Kotton Lab to recreate in a laboratory dish the lung cells that are needed. Those cells would be gene edited to correct the genetic mutation causing the disease and, last, transplanted back into the patient. Unlike getting a lung transplant, which involves heavy immunosuppressants so the body doesn’t reject the new organ, a patient would ideally tolerate their own cells without rejecting them, with no need for immunosuppression.

“This is our first attempt to build a future clinical model where we can start to think about reconstituting healthy tissue, the return of healthy tissue in the really diseased,” Ma says. Beyond their clinically focused goals, the researchers hope their work continues informing basic science questions, like how cells communicate with each other, what mechanisms regulate the identity of lung cells, and what makes them different from one another.

“Our work builds on a lot of basic science research that didn’t originally have a clinical goal,” says Ma, such as the invention of iPS cells. “My hope is that our papers can create a platform for other researchers in the community to generate more foundational knowledge that future translational studies will eventually build upon.”

Funding for these studies was provided by the National Institutes of Health National Heart, Lung, and Blood Institute and the Boston University Kilachand Multicellular Design Program Accelerator .

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Jessica Colarossi is a science writer for The Brink . She graduated with a BS in journalism from Emerson College in 2016, with focuses on environmental studies and publishing. While a student, she interned at ThinkProgress in Washington, D.C., where she wrote over 30 stories, most of them relating to climate change, coral reefs, and women’s health. Profile

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There are 11 comments on BU Researchers See Future Where Lung Disease Is Treatable, and Damaged Lungs Are Regenerated

Thanks for your work and hope it happens very soon.

My husband was just diagnosed with pulmonary fibrosis. After years of testing and being misdiagnosed with crohns disease and then switching medical systems and doctors. We are praying for a cure.

Being diagnosed with IPF on August 2018 and now on Esbriet three times per day. Struggling with shortness of breath. I wish you speedy success for the sake of the thousands who suffer from different lung diseases.

I’d like to learn more about Stem Cell treatment for lungs

I would like to volunteer for any future human trials.

Watching my father suffer from sarcoidosis that he contracted from agent orange poisoning in Vietnam, lung damage is a horrifying and slow death. Now my brother age 41, has been fighting his COPD lung disease for six years now. He is one of the most gentle souls I know. As I write this, he is currently back in the ICU. I pray that he lives long enough for a second chance like this would provide.

I’m with you Douglas.

Programs like these need to be expedited immediately! China has been doing this for years! Doctors are not being the voice of their patients! Big Pharmaceuticals & FDA rule what meds are allowed to us! Doctors don’t help patients to get into clinical trials! They are mortified if you ask for help. They don’t feel comfortable prescribing non-fda approved drug or to be involved in a trial! I’ve been fighting since 2015 with this broken medical system! I’m now doing stem cell therapy at a great financial cost! We need this therapy now & not years down the road through excessive testing! For God’s sake these patients only have at most 5 years to live!!! Now doctors are telling me that I need a lung transplant!!! That there’s no proof in stem cell therapy for lung disease! I disagree with them! I had stem cells 3 weeks ago. My lung function test today increased from a 40 to 53 on forced ventilation capacity! Now I can participate in clinical trials with these higher fvc numbers. I believe in stem cell therapy. My stem cell doctor in North Florida used to be a transplant surgeon. He told me that surgery opens up a new world of problems! It would be so very easy for stem cell therapy regenerate lungs & cure lung disease! But there’s no money in it for big pharma! That’s the name of the game Power & Money! I’m a registered nurse. Yes I’m angry & disappointed in the medical system. Ihave sarcoidosis. There hasn’t been a new drug developed for this disease since 1954!!!Why? Big Pharmaceuticals didn’t see a profit in it at that time! It’s going to take citizens to protest against big pharmaceuticals & FDA to get stem cell therapy regeneration for lung disease front & center. Please give patients a fighting chance……..

I sure hope (pray) this happens very very soon.

BU how soon could this happen it’s 2024 time to save lives people are suffering.

My husband passed away from Pulmonary Fibrosis. A cure can’t come soon enough. Thank you for all your research.

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Impact of COVID-19 pandemic among patients with lung and head and neck cancer assisted in a public cancer center in Brazil

• Gilson Gabriel Viana Veloso 1 ,
• Flávia Duarte Amaral 2 &
• Angélica Nogueira-Rodrigues 3  

BMC Cancer volume  24 , Article number:  539 ( 2024 ) Cite this article

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Metrics details

There is no updated national data regarding the real impact of the COVID-19 pandemic on delaying diagnosis and treatment among patients with lung, and head, and neck cancers in Brazil. This study aimed to analyze the COVID-19 pandemic impact on cancer diagnosis and clinical outcomes among lung, head, and neck cancer patients assisted in a tertiary cancer center in Southeastern Brazil, as well as to analyze these patients’ pretreatment clinical features.

Retrospective cohort of patients with lung or head and neck cancer assisted in a tertiary cancer center in southeastern Brazil between January/2019 and December/2021. To assess statistical differences among groups [i.e., cohort 2019 versus (vs.) 2020 and 2019 vs. 2021] chi-square test was used with a 5% significance level and 90% power for sample size calculation. Differences among baseline clinical features and sociodemographic characteristics were evaluated either by T-test for two samples or Fisher’s or Pearson’s chi-square test (for quantitative or qualitative variables). All utilized tests had a 5% significance level.

Six hundred fifty-two patients were included, 332 with lung and 320 with head and neck cancer; it was observed a significant decrease in oncologic treatment recommendations and increase in palliative care recommendation for patients with lung cancer, despite similar stages at diagnosis. During the COVID-19 pandemic, more pain symptoms were reported at the first Oncology assessment for patients with head and neck cancer ( p  < 0.05). Compared to 2019, head and neck cancer patients diagnosed in 2021 presented a worse initial performance status ( p  = 0.008). There was a statistically significant increase in survival for patients diagnosed with head and neck cancer in 2021 when compared to 2019 ( p  = 0.003).

Conclusions

This research highlights low survival rates for patients with lung and head and neck cancer in Brazil, even before the pandemic started, as consequence of advanced diseases at diagnosis at the public health system and clinical degrading features. Additionally, there was an increase incidence in both lung cancer and head and neck cancer despite no differences in clinical stage. This reflects how fragile is the public healthcare system even before facing an acute public health crisis such as the COVID-19 pandemic. Yet, the total impact on public health may follow for many years.

Peer Review reports

Cancer is now the first or second leading cause of death in over 60% of the countries, according to the World Health Organization (WHO) [ 1 ], and nearly 70% of cancer deaths occur in middle and low-income countries (LMICs) [ 2 ]. In 2020, 225,830 Brazilians died from the disease [ 3 ].

The Brazilian Ministry of Health estimates nearly 704,000 new cancer cases in the country for each year between 2023 and 2025 [ 3 ]. Regarding lung cancer, 32,560 new cases are expected per year, placing this tumor as the fourth most common cancer in the country [ 3 ]. Focusing on oral cavity and laryngeal cancers, nearly 15,100 and 7,790 new cases per year are expected, respectively [ 3 ].

Since the beginning of the coronavirus-19 pandemic (COVID-19), by the end of January 2023, over 6,7 million people have died from the disease worldwide, including nearly 700,000 Brazilians [ 4 ], and since its’ beginning, oncologists were concerned about its impact on patient care [ 5 ].

The overall distraction among health care systems due to COVID-19 may implicate deleterious effects on cancer patient assistance in the short and long-term follow-up [ 6 ] and quantifying the impact of delayed cancer diagnosis and treatment due to the pandemic in both the clinical stage and the prognosis is a complex task [ 7 ].

The main objective of this study was to analyze COVID-19 pandemic impact on cancer diagnosis among lung and head and neck cancer patients assisted in a tertiary cancer center in Southeastern Brazil as well as to analyze these patients’ pretreatment clinical features.

Materials and methods

Study protocol.

This was a retrospective cohort study at Santa Casa de Misericórdia de Belo Horizonte , a tertiary cancer center in Belo Horizonte, Southeastern Brazil. This study aimed to analyze whether the COVID-19 pandemic harmed patients with lung and head and neck cancers, yielding delayed diagnosis, more advanced clinical stage at diagnosis, and poorer outcomes in comparison with 2019, the year before the pandemic. For that aim, three cohorts were defined including patients diagnosed between 2019 and 2021, one cohort for each year. To proper collect and access data, two separate comparisons were defined: 2019 vs. 2020 and 2019 vs. 2021. In 2020 Brazil had major changes concerning lockdowns, restructure in the hospital to become a respiratory hospital for COVID-19 patients and major impact on increased deaths. In 2021, Brazil’s scenario started to change with vaccination coverage in January 2021, flexibilization of lockdown regimens and hospital’s regaining the opportunity to fully work as they usually did before the pandemic has started (i.e., 2019).

Population of analysis

Inclusion criteria included patients with a confirmed diagnosis of either head and neck cancer or lung cancer, above 18 years old, who had their first oncology assessment between January first, 2019, and December thirty first, 2021. Subjects could have had their first oncology assessment either by a hospital admission or on an ambulatory basis.

Exclusion criteria included: patients with inconclusive biopsies for malignant neoplasia, thyroid cancer, thymic tumors, and pleural mesothelioma. Those tumors were excluded from the final analysis due to different biological behavior in comparison to the other tumors here assessed.

Tumors were codified according to the International Classification of Diseases 10th edition (ICD-10) [ 8 ] as here described: C00, C01, C02, C03, C04, C05, C06, C07, C08, C09, C10, C11, C12, C13, C30, C31, C32, C33, C34, C43 and C80.

Data collection

Data collection was performed through a structured questionnaire developed by the authors aiming to assess all proposed objectives in this research. All charts were available for consultation at the hospital’s electronic system for assistant physicians.

For lifestyle habits associated with head and neck cancer, the following variables were included in the questionnaire: smoking and alcohol intake histories, divided into 2 categories: current or former and never; and, and body mass index (BMI – kg/m²), analyzed continuously and then categorized based on cutoffs for malnutrition (< 18,5 kg/m²), adequate (18,5–24,9 kg/m²), overweight (≥ 25,0 kg/m²), and obesity (≥ 30,0 kg/m²).

Sociodemographic variables included race and education level. Race was categorized into four categories: undeclared, Caucasian, black, and mixed race. Education level was categorized into 2 categories: ≤ 8 years of formal education and > 8 years of formal education. Financial status was initially included as a sociodemographic variable, however, due to a lack of data on charts (100% of misinformation) it was excluded.

To assess patients’ clinical features the following variables were included: clinical or pathologic stage, performance status at first oncologic assessment and after 6 months, treatment indication (including all modalities, i.e., surgery, chemotherapy, and/or radiotherapy), the indication of exclusive palliative care at first oncology assessment, pain symptoms reported, necessity of enteral nutrition, the indication of tracheostomy, and dental work-up before treatment started. The latter was used solely for patients with head and neck cancer. A dichotomized strategy was used (i.e., yes, or no) for the necessity of enteral nutrition, the indication of treatment, the indication of exclusive palliative care at first oncology assessment, pain symptoms, the indication of tracheostomy, and dental work-up before treatment.

Patients were staged accordingly to the TNM Classification of Malignant Tumors 8th edition by the American Joint Committee on Cancer [ 9 ]. Performance statuses were assessed based on the Eastern Cooperative Oncology Group (ECOG) scale, divided into six categories (range 0 to 5) [ 10 ]. Outcome analysis and objective response rate were based on the guideline for Response Evaluation Criteria for Solid Tumors (RECIST) 1.1 [ 11 ].

Two other variables included in this research were the time between primary biopsy and first oncology assessment and the time between the first appointment with an oncologist and the date of the first treatment. Means and standard deviation were calculated.

Overall survival analysis was calculated based on the date of diagnosis and date of death registered on the chart or loss of follow-up. Cutoff date for overall survival was January 15th, 2023. For the cause of death, patients were stratified into death due to baseline disease, due to COVID-19 infection or due to other cause (yes or no categories for all). Additionally, a dichotomous variable “death before treatment start” was included for those patients with treatment indication but who died before its’ beginning, also categorized into “yes” or “no”.

Statistical analysis

To assess statistical differences among groups [i.e., 2019 versus (vs.) 2020 and 2019 vs. 2021] a chi-square (χ²) test was used for two independent groups with a 5% significance level and 90% power for sample size calculation. To estimate measurement effectiveness a pilot study was performed by an independent statistician with 40 patients randomly selected from the patients described in Table  1 . Based on these data, the sample size was calculated on R statistic software version 3.5.1 with an effect of 0,2182. The minimum sample size for our planned analysis was then 298 patients (Fig.  1 ).

Sample size calculation

Differences among baseline clinical features and sociodemographic characteristics were evaluated either by T-test for two samples or Fisher’s or Pearson’s chi-square test (for quantitative or qualitative variables). T-test for 2 samples was used based on the central limit theorem, which states that in sample sizes above 5 or 10 per group, all means present with normal distribution, independently of data distribution [ 12 ]. All utilized tests had a 5% significance level (meaning a p -value ≤ 0,05).

All statistical analyses were performed on IBM SPSS Statistics (SPSS, version 23.0 for Windows; SPSS Inc, Chicago, Ill).

This study was submitted and approved by the Ethics Committee of Santa Casa de Misericórdia de Belo Horizonte (approval number 39,115,720,900,005,138). Since this is a retrospective cohort and there was a substantial number of reported deaths on the medical charts with no possibility for verbal or written consent, the need for informed consent was waived by Ethics Committee of Santa Casa de Misericórdia de Belo Horizonte .

Population characteristics

Six hundred fifty-two patients were included in the current analysis, 332 with lung cancer and 320 with head and neck cancer.

Focusing on the lung cancer patients, 87 patients were diagnosed in 2019, 124 in 2020 and 121 in 2021. In 2019 and 2020, the mean age at diagnosis was 66 years old, and 65 in 2021 (Table  1 ). In 2020, females were predominant; in 2019 and 2021 men were the majority. Baseline characteristics that showed a significant statistical difference among groups were smoking status (25% never smokers in 2020 compared to 10% in 2019, p -value 0.027) and race (25% of Caucasians in 2020 and 29% in 2021, compared to 17% in 2019, p -values 0.001 for both comparisons). Although non-significant, patients diagnosed during the pandemic presented with more pain symptoms (6% increase in 2020 and 12% increase in 2021, p -value 1.000 and 0.132, respectively) (Table  2 ). The time frame between first oncology assessment and initial treatment was shorter 20 days in 2020 compared to 2019 ( p -value 0.029). For the time gap analysis, we included patients with treatment recommendations (i.e., 68 patients in 2019, and = 74 patients in 2020). There was no difference when it comes to clinical stage and metastatic disease at diagnosis to all comparisons for patients with lung cancer (2019 vs. 2020 and 2019 vs. 2021).

Regarding the group with head and neck cancer, the mean age at diagnosis was 55.49 in 2019, 58.50 years in 2021, and 60.05 years in 2021 (Table  3 ); the latter with a statistically significant difference ( p -value 0.012). Males were predominant in all three years. The sole baseline characteristic that showed a significant statistical difference among groups was race (25% Caucasians in 2020 compared to 17% in 2019, and 28.9% of Caucasians in 2021 compared to 17% in 2019; p -value 0.000 for both comparisons). There was a 22% increase in primary tumor size (tumors classified as “T4”) among patients with head and neck cancer in 2020 in comparison to 2019 ( p -value 0.017). Presence of pain symptoms had nearly a 11% increase in 2020, and a 18% increase in 2021 when compared to 2019 ( p -value 0.002 and 0.029, respectively) (Table  4 ). In 2021, for the initial performance status, there was a 11% increase in category “2” ( p -value 0.008). Also, in 2021 the indication of tracheostomy had a 15% increase in comparison to 2019 ( p -value 0.043). For patients in the head and cancer group, there was no difference when it comes to clinical stage and metastatic disease at diagnosis to all comparisons (2019 vs. 2020 and 2019 vs. 2021). However, there was a tendency to the increased clinical stage in 2021 ( p -value 0.058 for the stratified clinical stage).

Outcomes and survival analysis

Regarding treatment recommendation for patients with lung cancer, including chemotherapy indication, it was observed a 12% decrease in treatment recommendations in 2020 compared to 2019 ( p -value 0.031), and 16% decrease in 2021 ( p -value 0.006), irrespectively of curative intention (i.e., first-line treatment also). Moreover, there was a 11% increase in the indication of exclusive palliate care at first oncology assessment in 2020 ( p -value 0.015) and 18% in 2021 ( p -value 0.001). All comparisons were with patients diagnosed in 2019, the year before the pandemic.

There were no statistically significant differences between patients’ outcomes for lung cancer when patients from 2019 to 2020 were compared (Table  5 ). For overall survival there was a non-significant reduction in 2020 survival [6 months (95% CI 3.18–8.81 months) in 2019 vs. 3 months in 2020 (95% CI 1.18–4.81)] (Table  5 ; Fig.  2 ). There was no statistically significant difference in objective rate response among patients with lung cancer in 2019 vs. 2021 group. Performance status after 6 months of first oncology assessment showed an increase in death rate after 6 months for 2021’s patients ( p  = 0.001). Even though there was a statistically significant difference regarding survival rate ( p  = 0.005), overall survival showed a non-significant 33% decrease in 2021 survival [6 months (95% CI 3.18–8.81 months) vs. 4 months (95% CI 2.41–5.59)] (Table  5 ; Fig.  2 ).

– Overall survival for patients with lung cancer, 2019–2021

There were no statistically significant differences between patients’ outcomes for head and neck cancer when patients from 2019 to 2020 were compared (Table  6 ). There was a statistically significant difference in survival rate in 2019 vs. 2021 group for patients with head and neck cancer, with a 20% decrease for patients from 2021 ( p -value 0.003). Additionally, performance status after 6 months of first oncology assessment showed an improvement after treatment with a 20% increase among patients categorized as “0” ( p  = 0.013). Differently from the lung cancer cohort, it was not observed a significant decrease in treatment recommendation or an increase in palliative care recommendation during the pandemic in the head and neck cancer cohort. Kaplan Meier’s curve for overall survival for head and neck cancer to all three years is demonstrated in Fig.  3 .

– Overall survival for patients with head and neck cancer, 2019–2021

The Santa Casa de Misericórdia de Belo Horizonte is a hospital with 1000 beds destined for public health care and is one of the biggest cancer centers in Minas Gerais state. The hospital is responsible for one-third of all oncology treatments on the providence. In 2019 24,666 oncology appointments, including patients for first assessment (hospital or ambulatory basis), patients in current anti-cancer treatment, patients in exclusive palliative care, and patients on follow-up after cancer remission. For 2020, the number of appointments were 24,547 and in 2021, 32,850. In addition, the Oncology service did not interrupt treatment assistance for cancer patients receiving chemotherapy and/or radiotherapy due to the pandemic. However, many surgeries were canceled due lack of beds in intensive care units (ICU) for post-operation observance since the ICU beds were relocated to patients with confirmed COVID-19 or acute respiratory distress. Also, during the COVID-19 pandemic, over 70% of these 1000 beds were turned into respiratory wings; such approach was also observed in other cancer centers in the country [ 13 ]. Worldwide the COVID-19 pandemic impacted cancer care; a global collaborative study across 54 countries [ 14 ] reported that in over 88% of the participating cancer centers there was challenges in providing adequate cancer care during the pandemic, including number of medical appointments, restricted access to medications, and missing on chemotherapy cycles. However, in this cancer center we were able to maintain the oncology wing in its’ full capacity and were able to increase the number of patients assisted.

Brazil is a middle-income country with over 207 million inhabitants (according to the 2022 census) [ 15 ]. Several low and middle-income countries are not prepared to provide adequate care to cancer patients, one of the reasons why high-income countries have higher survival rates [ 1 ]. The pillars of Brazil’s public health policies include equity, equality, and integrity to whoever seeks medical care in public health centers and Brazil’s Brazilian public health system provides free treatment to over 190 million people [ 16 ], including all cancer treatment modalities (i.e., surgery, chemotherapy, and radiotherapy) [ 17 ]. Since all these treatment options are fully funded by Brazilian’s government, patients’ assistance is completely free of charges, so, the resources offered to each patient is the same. Nonetheless, it is worth mentioning that the system may work with an important waiting list of medical appointments, diagnostic assessment, and treatment itself. Based on that, a Brazilian oncology patient loses nearly double of health years in comparison to some European countries and triple the time when compared to the United States of America [ 18 ]. Another fact that may impact overall cancer survival in Brazil is the difference between public health care and private care since there are several disparities among treatment options for locally advanced and advance diseases among these two groups. All these variables combined yield in low survival rate among cancer patients as it was demonstrated among the subjects included in this research.

Brazil has two specific laws regarding cancer treatment; the first one from 2012, known as the “60-day law” meaning that cancer patients have an upper limit of 60 days to initiate specific cancer treatment after diagnosis. The second one from 2019 is known as the “30-day law” meaning that highly suspicious patients have 30 days to fulfill all necessary diagnostic tests after symptoms have been reported to a medical physician [ 17 ]. Based on that, it was decided to assess among the subjects the time gap between the first oncology assessment and initial treatment; it was reported that in 2019 and 2021, the estimated time was close to 74 days, and for 2020, the estimated time was 53 days. National data indicates that most Brazilians receive a cancer diagnosis in the metastatic stage, reaching a peak of 200 days between the first reported symptom and biopsy release [ 17 ].

In this cohort, lung cancer patients diagnosed after the pandemic started shad a higher probability of not receiving chemotherapy and had a higher indication of exclusive palliative care, even though there was not a significant difference in clinical stage at diagnosis. To better define indication of best supportive care usually there’s a combination of ECOG scale plus functionality and nutritional status, and it was observed that patients were much more fragile than the pre-pandemic era and for our surprise, this scenario was irrespectively of clinical stage. Differences in treatment indication have not been observed in the head and neck cohort, but higher pain level at diagnosis was also observed.

In the lung cancer cohort 17.7% of patients had malnutrition, as for 35.6% in the head and neck cancer cohort. Brazilian nutritional status was updated in 2019, and results showed that 63% were above weight (overweight or obesity), 34.5% were eutrophic, and 2.5% were considered malnutrition [ 19 ]. In comparison to this study population, these updates showed that cancer patients may present with worst nutritional status than the general population, which is expected since involuntary weight loss is one of the first cancer symptoms. Moreover, patients with head and neck cancer may already experience reduced food intake before treatment starts [ 20 , 21 , 22 ], and patients with malnutrition have a higher risk of poor prognosis and worst treatment outcomes [ 23 ]. In this cohort, over 50% of patients with head and neck cancer patients needed enteral nutrition during treatment and that one-third suffered from malnutrition. Several aspects of the patient with head and cancer may alter due to malnutrition, such as impaired immune function, decrease in quality of life and interrupted treatments [ 20 ]. Pain tumor-related is an additional factor in weight loss [ 22 ], and we presented data with an increase in pain symptoms reported at diagnosis. The combination of our data based on nutritional status, and decreased functionality due to pain symptoms reinforce the findings of increased indication for exclusive palliative care it was found in this research.

Overall, pain symptoms were reported by 54.7% of the study population; 38% of patients in 2019 had pain symptoms reported. This number increased to 57% in 2020 and escalated to 31% in 2021. Here it must be highlighted that among patients with head and neck cancer, pain symptoms significantly increased after the COVID-19 pandemic started, whereas for lung cancer patients the reported increase was statistically non-significant. Since pain is one of the most challenging clinical features in cancer patients, it must be identified correctly and properly treated. Nearly 51% of all cancer patients report pain symptoms at some point during the disease (diagnosis, treatment, or exclusive palliative care) [ 24 ]. Patients with pain symptoms and delay medical care tend to seek self-medication, which may enhance treatment and clinical complications secondly to the mistreatment of their condition [ 25 ]. Lung cancer patients often report pain symptoms at diagnosis due to anatomic features of the tumor, such as bone and nerve invasion or metastatic disease, while patients with head and neck cancer may experience pain either due to the primary tumor or due to the treatment consequences, including surgery, radiation, or chemotherapy [ 24 ].

There was an increased number of lung cancer diagnoses on the hospital during the pandemic. For the lung cancer cohort, in 2020 there was an increase of 42.5% and in 2021 an increase of 39.1%. Concepcion et al. [ 26 ] reported an increase of 2.9% in 2020 and 3.34% in 2021 in total lung cancers diagnosed after the pandemic started but in much lower scale than it was found in this study. However, differently from what it was reported here, they showed a decrease in lung cancer death reports (-4.87% in 2020 and − 7.56% in 2021). Even though it was found an increased number of cancer diagnoses, Brazil had a decrease in such aspects during the pandemic, ranging from − 24.3% to -42.7% in some regions [ 27 ]; overall, up to 15,000 new cases were not diagnosed monthly due to COVID-19 [ 27 ]. Such data inference that oncology care varied in Brazilian territory during the pandemic – mainly due to lockdown recommendations and closed ambulatory services. Also, in contrast to these findings, a decreased incidence of lung cancer was observed by Kasymjanova et al. [ 28 ], with 34.7% less diagnosis but with more advanced stages during the COVID-19 pandemic. Regarding starting treatment with chemotherapy and/or radiotherapy, there was no significant delay.

Overall, there was no identification of statistical differences for the clinical stage at the lung cancer group, and it is worth mentioning that over 70% of subjects were metastatic at diagnosis [ 29 ]. The results presented by Lou et al. [ 30 ] also demonstrated no change in clinical stage at diagnosis for patients with lung cancer besides a shorter time-to-treatment in 2020 (38.92 days), like what it was found in this research. No change in clinical stage at diagnosis was also presented by Kizilirmak et al. [ 31 ]; stage IV disease was present in 59.31% of the pre-pandemic group and 65.35% of the pandemic group. Even though they did not find differences in lung cancer incidence between 2019 and 2020, Park et al. [ 32 ] identified a higher proportion of patients with locally advanced or metastatic disease after the COVID-19 pandemic started (2020 74.7% vs. 2109 62.7%).

Brazil does not provide thorax computerized tomography scans regularly due to high costs to the public health care system. There is no screening program for lung cancer in the country approved by Brazilian’s Ministry of Health, which might explain why Brazil has such high numbers of metastatic disease at diagnosis on a public health basis, which later will reflect in poorer outcomes since delayed diagnosis of lung cancer results in upper staging, decreased prognosis and lower survival rates [ 33 ]. Lung cancer has a 22.9% combined survival rate in five years [ 34 ], and clinical stage has an important role on these statistics, since clinical stage I ranges in survival rate from 92–68% in 5 years whereas patients with metastatic disease at diagnosis have a five-year survival rate of 10% [ 35 ].

Regarding the patients with head and neck cancer, there was an increase of 52.43% in 2020 and 37.8% in 2021. Nonetheless, Solis et al. [ 36 ] showed a 5–10% decrease in the number of new patients diagnosed with head and neck cancer after the COVID-19 pandemic, while several other international reports have documented a 22–43% decrease in the number of new diagnoses. Also, it was demonstrated patients with more advanced diseases when primary tumor size in 2020 was evaluated. In addition to the data here presented, the increased number of patients with tracheostomy indication may be related to such delayed diagnosis. Similarly, Tevetoğlu et al. [ 37 ], Flynn et al. [ 38 ], and Popovic et al. [ 39 ] also presented a cohort with patients presenting increased clinical stage at diagnosis among patients with head and neck cancer after the pandemic started. Although lymph node status is an important prognostic factor for these patients [ 40 ], this study did not find significant differences among all compared groups to this variable. The subgroup from 2021 did not showed differences among clinical stage, there was a tendency of more advanced diseased on the stratified staging. Similar results were presented by Clements et al. [ 41 ] who also did not find differences on symptoms and patients’ ECOG. The 5-year survival rates for head and neck cancer patients in general have a poor prognosis. The five-year survival rate varies between 30 and 70%, depending on the stage and location of the tumor [ 42 ]. In 2020 this cohort demonstrated a decreased survival in comparison to the pre-pandemic period. Similar results were cited by Peacok et al. [ 43 ]. As for 2021, there was a 20% increase in survival in comparison to 2019, but such significant difference may be due to a shorter follow-up in comparison to those patients from 2019, and perhaps such difference will balance after a 5-year follow-up.

In Brazil, public cancer centers receive a monthly amount of approximately $200,00 (R$ 1,100 Brazilian reais) from the government to treat patients with advanced lung cancer. For head and neck cancer the monthly amount of money range between $100,00 and $235,00 (R$ 571,00–1,300 Brazilian reais), irrespectively of clinical stage. The Brazilian healthcare system does not afford immunotherapy or direct target therapies for these tumors, except for gefitinib in patients with epidermal growth factor receptor (EGFR) mutations. In this context, that’s why Brazilian patients with lung, head and, neck cancer have access only to cytotoxic chemotherapy in contrast to all major recommendations for treatment worldwide [ 44 , 45 ]. While lung cancer survival improved tremendously over the past 15 years since precision medicine arose, the main goal for thoracic oncologists is to overcome the median overall survival of 8 months that chemotherapy usually achieves [ 46 ]. Over 85% of patients with lung cancer included in this study died. For patients with head and neck cancer, over 71% have passed. These data put in evidence the disparities when adequate treatment access is not available, setting back the recent advances in modern oncology.

The data collected had an expressive amount of missing data for baseline characteristics, especially for 2019’s patients, with special attention to sociodemographic features, which may have increased the statistical differences among groups in those aspects. That is one of the pitfalls that follow retrospective studies; such differences in exposure data among groups may alter the study estimates [ 47 ].

In conclusion, in a cohort of 652 lung and head and neck cancer patients treated in Brazil from 2019 to 2021, it was observed a significant decrease in oncologic treatment recommendations and increase in palliative care indication during the first two years of the pandemic in the lung cancer group, despite similar stages at diagnosis. Increased pain levels at diagnosis were observed in all patients during the pandemic compared to patients diagnosed at the year before it. This study also highlights low survival rates for patients with lung and head and neck cancer in Brazil, even before the pandemic, as a probable consequence of advanced diseases at diagnosis and limited access to best treatment options at the publica health system.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Abbreviations

Body mass index

Confidence interval

Coronavirus disease

Eastern Cooperative Oncology Group

Faculdades Ciências Médicas de Minas Gerais

Global Cancer Statistics

International Classification of Diseases

Intensive Care Unit

Low-and middle-income countries

Response evaluation criteria in solid tumors

Standard deviation

Standard error

Surveillance, epidemiology, and end results program

Classification of tumors

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Viana Veloso, G.G., Amaral, F.D. & Nogueira-Rodrigues, A. Impact of COVID-19 pandemic among patients with lung and head and neck cancer assisted in a public cancer center in Brazil. BMC Cancer 24 , 539 (2024). https://doi.org/10.1186/s12885-024-12255-0

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Researchers review findings and clinical messages from the Women’s Health Initiative 30 years after launch

Data from influential study underscore the importance of personalized and shared decision-making to support the health of postmenopausal women

WHAT: A new review in JAMA highlights key findings and clinical messages from the Women’s Health Initiative (WHI), the largest women’s health study in the United States. The WHI is supported by the National Institutes of Health’s National Heart, Lung, and Blood Institute (NHLBI), and was created to study factors that may reduce risks for cardiovascular disease, cancer, hip fractures, and other conditions in postmenopausal women. More than 68,000 women enrolled in clinical trials between 1993 and 1998 and were followed for up to 20 years.

After reviewing these long-term data, the researchers explain the primary findings:

Hormone therapy and menopause. The WHI study found that estrogen or a combination of estrogen and progestin, two types of hormone replacement therapies, had varying outcomes with chronic conditions, and the evidence does not support the use of these therapies to reduce risks for chronic diseases, such as heart disease, stroke, cancer, and dementia. The study was not designed to assess the effects of FDA-approved hormone therapies for treating menopausal symptoms, the benefits of which had been established before the WHI study began.

The authors reinforce the importance of women making shared decisions with physicians about the benefits or risks of taking hormone therapy during menopause. For example, women younger than age 60 with low-to-average risk for cardiovascular disease and breast cancer who want to take hormone therapy may experience greater health benefits than risks during early menopause to treat moderate-to-severe symptoms, such as bothersome hot flashes or night sweats.

Calcium and vitamin D supplements and bone fractures. A combined calcium and vitamin D supplement was not associated with reduced risks for hip fractures among postmenopausal women at average risk for osteoporosis, according to the study. However, the authors note that supplements can help fill nutrient gaps among women who do not meet the daily recommended intake for these nutrients . Therefore, women with questions about adequate intake and levels should consult with their healthcare provider.

Low-fat diets and cancer. A low-fat dietary pattern with at least five daily servings of fruits and vegetables and increased grains did not reduce the risk of breast or colorectal cancer. However, upon subsequent analyses during the follow-up period, researchers found that this type of eating pattern was associated with a reduced risk of death from breast cancer.

Findings from the clinical trials and study observations can vary based on multiple factors, such as age and underlying cardiovascular disease risks, so women ages 50 and older should work with their clinicians to make individualized and shared medical decisions, the researchers noted.

STUDY: Manson, JE, Crandall CJ, Rossouw JE, et al. The Women’s Health Initiative randomized trials and clinical practice: A review. JAMA ; 2024. Doi: 10.1001/jama.2024.6542.

WHO: Candice A. Price, Ph.D., program director of the epidemiology branch, located within the Division of Cardiovascular Sciences at NHLBI, is available to discuss this review.

About the National Heart, Lung, and Blood Institute (NHLBI):  NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visit  www.nhlbi.nih.gov .

About the National Institutes of Health (NIH):  NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit  www.nih.gov .

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Research shows link between pollution and heart risks in residents of the city of São Paulo, Brazil

by Emilio Sant'anna, FAPESP

The relationship between living in a polluted city like São Paulo (Brazil) and lung disease or cancer is well known. But the problems go further. Unprecedented research shows that long-term exposure to air pollution is directly linked to increased heart risks in residents of the capital of the state of the same name. People with high blood pressure are at even greater risk.

The study, published in the journal Environmental Research , was conducted by researchers from the University of São Paulo. The research shows that cardiac fibrosis, an indicator of heart disease, is related to the duration of exposure to black carbon particles, an indicator of air pollution .

The researchers analyzed the autopsies of 238 people and epidemiological data to measure this association. They also interviewed relatives of the victims to gather information on risk factors such as a history of smoking and hypertension. From macroscopic observation of lung tissue, they determined the presence and amount of the black carbon fraction in the lungs. Myocardial samples revealed the cardiac fibrosis fraction.

The results showed a significant association between the black carbon fraction in the lungs and cardiac fibrosis in the individuals studied. This means that the longer a person is exposed to pollution, the more likely they are to develop fibrosis. "This data highlights the crucial role of autopsy in investigating the effects of the urban environment and personal habits in determining diseases," says one of the authors of the study, pathologist and USP professor Paulo Saldiva.

In addition, it was found that the risk is increased for hypertensive individuals. Among them, the presence of the heart disease marker increases with the increase in the presence of the pollution exposure indicator, both in smokers and non-smokers. Among non-hypertensive individuals, the highest risks were observed mainly among smokers.

Hypertension, or high blood pressure , is a disease that can be silent and without symptoms. According to the Brazilian Ministry of Health, the mortality rate has increased in ten years from 11.8 deaths per 100,000 inhabitants in 2011 to 18.7 in 2021. Around 60% of the country's elderly suffer from hypertension.

When hypertension is silent, pollution is not always visible. In some cases, however, it is possible to know where it is most harmful. Exposure to pollution within the same city depends on factors such as people's habits and commutes.

"We can say that there are two indicators of pollution, one measured by the CETESB [São Paulo State Environmental Corporation] network, which is objective. And another related to how much each individual is exposed to," Saldiva says. "In other words, the level of concentration of environmental pollution doesn't mean the same dose is received by everyone. If you're in a traffic corridor for hours, you receive a higher dose because the concentration of that environment is particularly higher."

Saldiva explains that various factors, such as hypertension itself, influence the development of cardiac fibrosis, and that pollution has now been shown to be one of them. "The question was, 'Is pollution big enough to show up in this photo?' It is, and it was the first time in the world that it had been demonstrated in humans. That's the difference in this work," he points out.

According to the doctor, the study was only possible thanks to the work carried out 24 hours a day, 365 days a year by the city's Death Verification Service (SVO). He says that the support of the USP Medical School and FAPESP, in agreements signed in the past with the SVO, has built up a vast body of processes and information that today lead to new scientific possibilities.

USP's research provides evidence of the impacts of air pollution on cardiovascular health and highlights the need for effective measures to reduce the population's exposure to this evil. Implementing measures such as reducing vehicle emissions, promoting sustainable public transport in the city, and promoting clean energy sources are effective strategies for mitigating the impacts of air pollution on public health.

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Researchers reveal a new approach for treating degenerative diseases

Insights on the proteasome reveal a therapy target for misfolded protein diseases.

Proteins are the workhorses of life. Organisms use them as building blocks, receptors, processors, couriers and catalysts. A protein's structure is critical to its function. Malformed proteins not only fail to carry out their tasks, they can accumulate and eventually gum up the inner workings of cells. As a result, misfolded proteins cause a variety of degenerative diseases, from Alzheimer's and Parkinson's to the blinding disease retinitis pigmentosa. These disorders are currently incurable.

A paper out of UC Santa Barbara reveals a new connection between a particular ion transport protein and the cell's garbage disposal, which grinds up misfolded proteins to stave off their toxic accumulation. The results, published in Developmental Cell, identify a target for treating these debilitating conditions.

"By studying basic cell biology in fruit fly ovaries, we stumbled upon a way to prevent neurodegeneration, and we think this has potential applications in the treatment of some human diseases," said senior author Denise Montell, Duggan Professor and Distinguished Professor in the Department of Molecular, Cellular, and Developmental Biology.

For 35 years, Montell's lab has studied the movement of cells in fruit fly ovaries. It might seem esoteric, she is the first to admit, but it provides a fantastic model for cell mobility. "And cell movement underlies embryonic development, drives wound healing and contributes to tumor metastasis," she explained. "So it's a really fundamental cell behavior that we care to understand deeply."

The setting and characters

The star of this paper is a gene called ZIP7 , which encodes a protein of the same name. In previous work, Montell's team came across a mutation in this gene that impaired cell mobility, piquing their interest.

The ZIP7 protein ferries zinc ions within a cell. These ions are exceedingly rare within the cytoplasm but abundant in proteins where they often form part of the architecture and catalyze chemical reactions. "ZIP7 is conserved in evolution from plants to yeast to flies to humans," Montell said. "So it's doing something really fundamental, because it's been around for a really long time."

ZIP7 is also the only zinc transporter found in the endoplasmic reticulum, a membranous structure where a cell makes proteins destined for the outer membrane of the cell or for secretion out of the cell. About a third of our proteins are made here.

If ZIP7 is our protagonist, then misfolded proteins and their disposal are the theme of the study. For proteins, function follows form. It's not enough to have the right ingredients, a protein must fold correctly to function properly. Misfolded proteins are responsible for a host of diseases and disorders.

But proteins will sometimes misfold even in a healthy cell. Fortunately, cells have a quality control system to deal with this eventuality. If the error is small, the cell can try folding it again. Otherwise, it will tag the misfolded molecule with a small protein called ubiquitin and send it out of the endoplasmic reticulum (ER) for recycling.

Waiting in the cytoplasm are structures called proteasomes, the "garbage disposals" of the cell. "It literally chews up the protein into little pieces that can then be recycled," Montell said.

"But if the garbage disposal gets overwhelmed -- somebody puts too many potato peels in there -- then the cell experiences ER stress." This triggers a response that slows down protein synthesis (pauses our potato prep) and produces more proteasomes so that the system can clear the backlog of waste. If all this fails, the cell undergoes programmed death.

The plot thickens

Co-lead author Xiaoran Guo, Montell's former Ph.D. student, saw that loss of ZIP7 caused ER stress in the fruit fly's ovary. So she set out to determine if this stress was the reason the cells lost their mobility. Indeed, inducing ER stress with a different misfolded protein also impaired cell migration.

When Guo over-expressed ZIP7 in these cells, the backlog of misfolded proteins disappeared, the ER stress vanished, and the cells regained their mobility. "I was so surprised that I had to question myself if I had done everything correctly," Guo said. "If this was real, just ZIP7 alone must be very potent in resolving ER stress."

What's more, the misfolded protein she used, called rhodopsin, contains no zinc in its structure. This led Guo to suspect that ZIP7 must be involved somewhere in the degradation pathway. Co-lead author, and fellow doctoral student, Morgan Mutch used a drug to block the proteasome from degrading misfolded rhodopsin and observed that this negated the beneficial effect of ZIP7. She concluded that ZIP7 must be acting somewhere before the proteasome munches up the misfolded protein.

The authors created four modified ZIP7 genes: two mutations disrupted the protein's ability to carry zinc, while the other two left this unchanged. They discovered that zinc transport was critical in reducing ER stress.

At this point, a new character enters our story: the enzyme Rpn11, which forms part of the proteasome. Much like trying to stuff a large head of broccoli down the disposal, misfolded proteins with ubiquitin tags don't fit into the proteasome. Rpn11 snips off these tags, enabling the misfolded protein to slip into the proteasome core for disassembly. Zinc is essential forRpn11 to catalyze the removal of ubiquitin.

"I was very surprised, and then excited, when I saw that increasing ZIP7 expression almost completely prevented the buildup of those ubiquitin-tagged proteins," Mutch said. "We were expecting the opposite result."

Mutch determined that ZIP7 was critical in supplying zinc to Rpn11, enabling it to trim the tags that label defective proteins so that they fit into the structure that actually breaks them down. Blocking the Rpn11 enzyme confirmed this hypothesis.

"That feeling when you discover something new, something no one has figured out before, is the best feeling for a scientist," Mutch added.

A potential therapy

The results suggest that overexpressing ZIP7 could form the basis for treating a variety of diseases. For instance, misfolded rhodopsin causes retinitis pigmentosa, a congenital blinding disease that is currently untreatable. Scientists already have a strain of fruit flies with the mutation that causes a similar disease, so the team overexpressed the ZIP7 gene in these flies to see what would happen.

"We found that it prevents retinal degeneration and blindness," Montell said. Every single one of the flies with mutant rhodopsin usually develops retinitis pigmentosa, but a full 65% of those with overactive ZIP7 formed eyes that respond normally to light.

Montell's lab is now collaborating with Professor Dennis Clegg, also at UC Santa Barbara, to further investigate the effect of ZIP7 in human retinal organoids, tissue cultures that bear a mutation that causes retinitis pigmentosa. This project was originally funded by the National Institute for General Medical Sciences. For the next three years it will be supported by a $900,000 grant from the Foundation Fighting Blindness so Montell, Clegg and their colleagues can test the hypothesis that ZIP7 gene therapy will prevent blindness in retinitis pigmentosa patients.

What's more, proteasome capacity declines as we get older, contributing to many classic signs of aging and increasing the probability of age-related degenerative diseases. Therapies targeting ZIP7 could potentially slow the development or progression of these ailments, as well. They've already yielded promising results extending fruit fly lifespan.

"This is a poster child for fundamental, curiosity-driven research," Montell said. "You're just studying something because it's cool, and you follow the data and end up discovering something you never set out to study, possibly even a cure for multiple diseases."

• Human Biology
• Lung Cancer
• Sickle Cell Anemia
• Huntington's Disease
• Schizophrenia
• Mad Cow Disease
• Heat shock protein
• Biochemistry

Story Source:

Materials provided by University of California - Santa Barbara . Original written by Harrison Tasoff. Note: Content may be edited for style and length.

Journal Reference :

• Xiaoran Guo, Morgan Mutch, Alba Yurani Torres, Maddalena Nano, Nishi Rauth, Jacob Harwood, Drew McDonald, Zijing Chen, Craig Montell, Wei Dai, Denise J. Montell. The Zn2+ transporter ZIP7 enhances endoplasmic-reticulum-associated protein degradation and prevents neurodegeneration in Drosophila . Developmental Cell , 2024; DOI: 10.1016/j.devcel.2024.04.003

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