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10.1172/JCI183836
1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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1Department of Medicine, National Jewish Health, Denver, Colorado, USA.
2Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
3Rocky Mountain Regional Veteran Affairs Medical Center, Aurora, Colorado, USA.
4Department of Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University, School of Medicine, Stanford, California, USA.
5Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
6Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA.
7Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
8Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
9Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Address correspondence to: David A. Schwartz, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA. Email: david.schwartz@cuanschutz.edu.
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Published January 2, 2025 - More info
Published in Volume 135, Issue 1 on January 2, 2025
AbstractIdiopathic pulmonary fibrosis (IPF) is etiologically complex, with well-documented genetic and nongenetic origins. In this Review, we speculate that the development of IPF requires two hits: the first establishes a vulnerable bronchoalveolar epithelium, and the second triggers mechanisms that reprogram distal epithelia to initiate and perpetuate a profibrotic phenotype. While vulnerability of the bronchoalveolar epithelia is most often driven by common or rare genetic variants, subsequent injury of the bronchoalveolar epithelia results in persistent changes in cell biology that disrupt tissue homeostasis and activate fibroblasts. The dynamic biology of IPF can best be contextualized etiologically and temporally, including stages of vulnerability, early disease, and persistent and progressive lung fibrosis. These dimensions of IPF highlight critical mechanisms that adversely disrupt epithelial function, activate fibroblasts, and lead to lung remodeling. Together with better recognition of early disease, this conceptual approach should lead to the development of novel therapeutics directed at the etiologic and temporal drivers of lung fibrosis that will ultimately transform the care of patients with IPF from palliative to curative.
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease, characterized by heterogeneous subpleural patches of fibrotic remodeled lung, that follows a bronchocentric distribution (1–3). The median survival is 3–5 years after diagnosis (1). While the etiology of IPF was initially unknown (thus, the nomenclature), we now understand that IPF is etiologically complex, with well-documented genetic and nongenetic origins. Lung fibrosis genetic risk variants demonstrate an autosomal dominant pattern of inheritance with incomplete penetrance (4), and in aggregate, these genetic risk variants account for at least 30% of the etiology of IPF (5). Cigarette smoke (6) and aging (7–9) also promote the development of IPF. How these nongenetic factors interact with specific genetic variants is not clear, but cigarette smoke and aging are known to contribute to epigenetic programming of the lung. Genetic susceptibility, epigenetic programming, and maladaptive homeostatic responses likely interact in ways that are yet to be described, reprogramming cells toward a fibroproliferative phenotype in the distal lung.
Genetic studies have identified dozens of rare and common genetic risk variants for IPF within key biological pathways that primarily affect the bronchiolar and alveolar epithelia (Table 1) (10). Although the gain-of-function MUC5B promoter variant is the dominant risk factor for this disease (11), accounting for at least 50% of the genetic risk of developing IPF (5), multiple biological mechanisms involving dysregulation of host defense, cell adhesion, telomere biology, mitotic spindle assembly, surfactant protein biology, and GTPase activity are implicated in the risk of developing IPF. Importantly, all genetic variants, except possibly a rare missense mutation in SFTPC (12), demonstrate incomplete penetrance for lung fibrosis, suggesting that ectopic expression or gain/loss of function of these genes establishes a biologically vulnerable phenotype that requires subsequent insults to trigger development of IPF.
Table 1Common and rare IPF risk variants
Multiple types of environmental exposures promote the development of fibrotic interstitial lung disease (ILD; IPF is a type of ILD) and are candidate second hits within the appropriate genetic context. The dominant nongenetic factors that enhance the risk of IPF are aging (1, 7, 8, 13) and cigarette smoking (6, 14, 15), with each one-year increase in age associated with an approximately 6% increase in IPF prevalence (16) and cigarette smoking associated with an approximately 3- to 5-fold increase in the risk of IPF (4, 6). Aerosolized pollutants resulting from wildfires and other combustions, ozone, particulate matter (PM2.5 and PM10), metal dust, asbestos, farming, and livestock (14, 15, 17–19) have also been associated with interstitial lung abnormalities (considered a sign of early ILD or IPF, ref. 20), IPF incidence (21), and acute exacerbations of IPF (22–25). These nongenetic IPF risk factors suggest that mechanisms involving particle deposition (20, 25, 26), mucociliary dysfunction, epithelial injury with attendant persistent inflammation (27–29), stem cell exhaustion (30–32), and cell senescence (32–35) represent key drivers of the persistent fibrotic process. These risk factors may also be influenced by genetic variants. Such observations led to the two-hit hypothesis (36); in our model, the first hit establishes a vulnerable bronchoalveolar epithelium, and the second triggers mechanisms that reprogram distal epithelia to initiate and perpetuate a profibrotic phenotype (Figure 1).
Figure 1Two-hit model of pulmonary fibrosis. We postulate that genetic and epigenetic etiologic drivers establish a vulnerable bronchiolar and alveolar epithelia (first hit) and that this results in homeostatic adaptation without the development of lung fibrosis. Persistent and progressive lung fibrosis can be triggered by a second hit (such as tobacco smoke, air pollution, inflammation, and/or aging) to the bronchiolar and alveolar epithelia, resulting in epithelial reprogramming, endoplasmic reticulum (ER) stress, unfolded protein response (UPR), apoptosis, and ultimately leading to fibroblast accumulation and activation, fibrosis, and abnormal lung remodeling.
In this Review, we discuss the two-hit hypothesis with an emphasis on MUC5B as the primary genetic risk factor, as it is an emerging aspect of IPF pathogenesis that has not been comprehensively addressed in prior reviews. We will also discuss how detrimental endoplasmic reticulum (ER) stress involving apoptosis, a persistent cycle of injury and repair, and activation of lung fibroblasts develop following additional damage to the terminal respiratory bronchiole. While IPF has been further characterized by dysregulation of immune cells and noncoding RNA signaling, these contributions are beyond the scope of the present discussion, and readers are directed elsewhere for comprehensive reviews of these topics (37, 38).
Mechanisms initiating epithelial vulnerabilityPeripheral remodeling and loss of alveolar gas exchange surfaces in IPF highlight a need to understand how vulnerable lung epithelial cells may be reprogrammed to perpetuate a profibrotic phenotype. Early work emphasized alveolar type II (ATII) cells as the main targets of injury and drivers of fibrosis. Recently, multipotent epithelial progenitors that give rise to both terminal airway and alveolar cells have been shown to be susceptible to injury and may contribute to fibrosis (39–51). When challenged with ongoing exposures, a rodent model demonstrated that epithelial progenitors fail to return to homeostasis and instead promote persistent injury and fibrosis through maladaptive repair, which was exacerbated in the context of enhanced MUC5B expression (29).
Aberrant progenitors and regenerative epithelia. Findings from murine and human studies demonstrate that fibrosis in IPF persists owing to sustained disruption of tissue homeostasis and recognize the central role of progenitor cells and cell populations in aberrant transitional states. The specific cell types and pathways involved in homeostatic repair and disease will likely depend on the model organism studied, owing to anatomical differences in the distal lungs among humans, nonhuman primates, and rodents (Figure 2). Yet, a subset of Wnt-responsive ATII cells proliferate in response to injury and differentiate into alveolar type I (ATI) cells to repair the alveolar epithelium following injury in mice (52, 53) and have also been shown to possess progenitor function in human organoid cultures. During fibrosis, ATII cells exhibit a transitional morphology and gene expression profile consistent with ineffectual/stalled differentiation to ATI cells (54, 55). In clustered, cystic airspaces termed honeycomb cysts in IPF, this transitional state is marked by expression of one or more keratin genes (KRT5 and KRT14) and in simple cysts, by KRT8 and KRT18 in the bleomycin mouse model (11, 56, 57). Genetic variants in the KRT8 locus are associated with IPF, and KRT8+ epithelial cells have a direct pathologic role in driving fibroblast activation, proliferation, and collagen deposition in the bleomycin model (58). Molecular pathways associated with these transitional states currently include TGF-β, p53, Notch, Sonic hedgehog (Shh), bone morphogenetic protein (BMP), and Wnt (45, 58–64).
Figure 2Model of the development of vulnerable bronchoalveolar epithelium as a contributing pathway to persistent pulmonary fibrosis. (A) In the healthy lung, the bronchoalveolar epithelium consists of proximal epithelial cells in the terminal airways (basal cells, ciliated cells, club cells, and goblet cells) and alveolar type II (ATII) and type I (ATI) cells in the alveoli and minimal if any expression of MUC5B. Identified epithelial progenitor populations, including ITGB4β+/H2-K1hi cells in the conducting airways, BASCs at bronchoalveolar ducts in mice, and newly identified TASC, RASC, and AT0 cells in the preterminal and terminal respiratory bronchioles in humans, nonhuman primates, and ferrets are thought to be quiescent in the absence of injury. (B) In the presence of genetic variants (e.g., MUC5B), increased expression of MUC5B protein in goblet cells, and other cell types that do not typically express MUC5B protein (e.g., ATII cells), causes homeostatic ER stress, resulting in a vulnerable state that primes epithelial cell responses to subsequent injury. Repair of the bronchiolar and alveolar epithelia (B, left) is governed by epithelial cell/fibroblast/immune cell interactions near the site of injury that direct facultative epithelial progenitor cell (ATII) proliferation and differentiation into ATI cells and suppress fibroblast proliferation/activation. In addition, epithelial progenitor cells located at sites distant to the site of injury are activated and migrate to the injured alveolus (ITGB4β+/H2-K1hi cells, BASCs) to restore formation of the air/blood barrier. However, in the context of repetitive secondary injuries (below B), the persistent and enhanced ER stress induces detrimental responses in the vulnerable epithelium, causing epithelial dysfunction during injury/repair, as indicated by aberrant epithelial cell differentiation, arrested transitional cell states, and activation of aberrant basaloid cells in the alveoli. (C) This leads to profibrotic fibroblast and pericyte activation, proliferation, and excess extracellular matrix deposition. The consequence of respiratory bronchiole dropout in patients with early-stage IPF and the role of RASCs, TASCs, and AT0 progenitor populations in homeostatic repair versus a persistent fibrotic state has yet to be determined.
In murine airways, bronchioles terminate directly into alveolar duct openings at the bronchioalveolar duct junction and are populated by bronchioalveolar stem cells (BASCs) that exhibit transcriptional profiles of both airway secretory and ATII cells (SCGB1A1 and SFTPC) (41). Following distal lung injury, BASCs can differentiate into airway or alveolar epithelial cells (39) or to proximal epithelial cells after airway-specific injury (40–42). Separately, rare ITGB4β+H2-K1hi progenitor cells located in proximal airways were shown to engraft into bleomycin-injured mouse lungs following intratracheal transplantation with subsequent differentiation into ATII cells (43, 44). Intralobular serous cells that coexpress SCGB3A2+SCGB1A1+ and KRT5, a marker of airway basal stem cells, were identified in an influenza acute lung injury model and may contribute to bronchiolization in IPF (45–47). These observations suggest that the plasticity of existing progenitor cells localized at the site of injury and the migration of anatomically distant epithelial cells following injury may dictate normal versus excessively fibrotic repair outcomes.
In humans, terminal respiratory bronchioles and alveolar ducts are separated by structures called respiratory bronchioles that contain airway, alveolar, and BASC-like cells. Among these, airway epithelial progenitors termed terminal airway secretory cells (TASCs, marked by SCGB3A2+SFTPB+) (48), respiratory airway secretory cells (RASCs, marked by SCGB3A1+SCGB3A2+SFTPB+CEACAM6+) (49, 50), and AT0 cells (marked by SCGB3A2+SFTPB+SFTPC+) (50) were identified as cell types of interest (Figure 2). Loss of anatomical structures in humans, such as terminal respiratory bronchioles and bronchoalveolar ducts that house the newly identified TASC/RASC populations, may play a significant role in the aberrant repair process that occurs in fibrosis (16). Recent work has demonstrated a loss of progenitor ATII cells and an increase in the number of BASCs during aging (65). It will be critical for the field to address the initial role and eventual loss of these progenitor populations in IPF. The role of genetic risk variants and/or aging in the generation of a vulnerable epithelium and potential consequences for the differentiation trajectory of these cells in vivo are incompletely understood. Ho
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