Version May 2024
INTRODUCTION — Idiopathic pulmonary fibrosis (IPF), previously known as cryptogenic fibrosing alveolitis (CFA) in Europe, is a chronic, relentlessly progressive fibrotic disorder of the lower respiratory tract that typically affects adults over the age of 40 [1]. IPF is the most common type of the idiopathic interstitial pneumonias (IIPs) [1,2].
The histopathologic pattern associated with the clinical diagnosis of IPF is referred to as "usual interstitial pneumonia" (UIP). UIP can also be seen in other fibrotic lung diseases associated with connective tissue diseases, chronic hypersensitivity pneumonitis, and asbestosis. (See "Asbestos-related pleuropulmonary disease".)
An overview of the pathogenesis of IPF, including the central role of fibroblast proliferation and abnormal collagen metabolism will be presented here. The clinical manifestations, differential diagnosis, evaluation, and treatment of IPF are discussed separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Treatment of idiopathic pulmonary fibrosis".)
HISTOPATHOLOGY — The characteristic histopathologic features of usual interstitial pneumonia (UIP) in patients with idiopathic pulmonary fibrosis (IPF) include abnormal proliferation of mesenchymal cells, varying degrees of fibrosis, overproduction and disorganized deposition of collagen and extracellular matrix, and distortion of pulmonary architecture and subpleural cystic airspaces (3 to 10 mm diameter) called honeycomb cysts. Fibroblast foci are clusters of fibroblasts and myofibroblasts that lie in continuity with the established fibrosis and are a characteristic histologic feature of UIP (picture 1) [1,3-6].
The end result of the fibrotic process is a complex reticulum that is highly interconnected and extends from pleura into the underlying parenchyma [7] (image 1). The pathology of UIP in comparison with other interstitial pneumonias is discussed in greater detail separately. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Usual interstitial pneumonia'.)
ANIMAL MODELS — Much of the research into mechanisms of disease pathogenesis in idiopathic pulmonary fibrosis (IPF) comes from work with animal models of pulmonary fibrosis (eg, intratracheal instillation of bleomycin). Unfortunately, animal models of lung fibrosis do not translate perfectly to human IPF because most animal models have a prominent inflammatory cellular component as a tissue response to injury. By comparison, usual interstitial pneumonia (UIP), which is the characteristic histologic pattern of human IPF, typically lacks inflammatory cells in the fibrotic lungs [1-6]. Subepithelial fibroblast foci, the histologic hallmark of UIP (picture 1), are absent in most animal models of pulmonary fibrosis. Nevertheless, there are sufficient similarities between some animal models and human disease to be able to develop a number of insights and hypotheses about IPF pathogenesis [8,9].
INITIATION — The precise factors that initiate the histopathologic processes observed in idiopathic pulmonary fibrosis (IPF) are unknown. Certain risk factors are associated with IPF, including cigarette smoking, viral infection, environmental pollutants, chronic aspiration, genetic predisposition, and drugs [10,11]. However, none of these risk factors adequately explains the extensive remodeling and progressive nature of IPF, or the increase in incidence of fibrosis with advancing age.
It is possible that nonspecific injury to the epithelial barrier and pulmonary parenchyma, such as might be inflicted by these risk factors, initiates the disease process of IPF in susceptible individuals.
Genetic predisposition — A genetic predisposition to pulmonary fibrosis is supported by reports of families with several affected members (familial pulmonary fibrosis) and by genome wide association studies [3,10,12-28]. However, the precise genetic and host susceptibility factor(s) that determine the phenotypic expression and clinical manifestations of sporadic IPF remain unknown [10].
Investigations have identified many gene variants that may play a role in the pathogenesis of pulmonary fibrosis [16-24,26-36]:
Surfactant proteins — Variants of surfactant proteins A2 (SP-A2) and C (SFTPC) have been identified in several families with IPF [16-18]. Variants in the adenosine triphosphate binding cassette A3 (ABCA3) gene may affect the course of SFTPC-related IPF [14,19].
MUC5B — A genome-wide linkage scan identified a risk locus for IPF on chromosome 11, and further fine mapping of that locus found a common variant in the promoter of the gene encoding mucin 5B (MUC5B) [20]. This variant was present in 34 percent of subjects with familial pulmonary fibrosis, 38 percent of those with IPF, and 9 percent of controls. In a separate study, a MUC5B promoter single nucleotide polymorphism was significantly associated with IPF, but not lung fibrosis in sarcoidosis or systemic sclerosis [29]. Furthermore, this same genetic variant is associated with interstitial lung abnormalities on chest computed tomography (CT) in the general population [33,34]. MUC5B expression in lung tissue is 14 times higher in subjects with IPF compared with unaffected subjects. Overall, MUC5B variants account for three times the risk of IPF than 13 other susceptibility variants combined [36].
Telomerase-related genes — Variants in telomerase-related genes (eg, TERT, RTEL1,TERC, DKC1, TINF2), which cause shortened telomeres, have been identified in about 25 percent of sporadic IPF and in about 15 percent of families with familial pulmonary fibrosis [21-25,30,37-42]. Rare variants in TERT and RTEL1 significantly contributed to the overall risk for IPF in a large cohort of over two thousand patients with IPF [43]. However, the relationship between IPF, telomerase activity, and telomere length appears complex. Patients with sporadic IPF and telomere shortening do not necessarily have identifiable variants in the telomerase genes, and telomerase activity is induced in a greater proportion of lung fibroblasts from patients with IPF than controls [31]. (See "Dyskeratosis congenita and other telomere biology disorders" and "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Dyskeratosis congenita and other telomere abnormalities' and "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Inherited bone marrow failure syndromes'.)
As an example of an implicated telomerase-associated gene, a study of 25 kindreds of familial interstitial pneumonia (FIP) identified nine associated loss-of-function, rare variants in the gene encoding the regulator of telomere elongation helicase 1 (RTEL1) [44]. Missense and loss-of function variants were also associated with IPF in a whole genome sequencing analysis of a large cohort [43]. RTEL1 is a DNA helicase that regulates telomere replication and stability. The rare variants identified in the kindred study segregate with FIP and are associated with very short telomeres in peripheral blood mononuclear cells. In 163 additional FIP kindreds, heterozygous variants of RTEL1 were found in eight families (approximately 5 percent).
Genome-wide association studies (GWAS) have confirmed associations between idiopathic interstitial pneumonias (IIPs) and the telomerase gene TERT, the mucin gene MUC5B, telomere elongation helicase 1, RTEL1, and a region near the TERC telomerase gene (3q26) [28,32].
Other genes — Additional genes contributing to a predisposition to IPF were identified using genome-wide association studies in conjunction with investigations of rare variants or gene expression in patients with IPF.
●A-kinase anchoring protein 13 – A genome-wide association study in patients with IPF of European origin in the United Kingdom, with confirmation using independent datasets from the Chicago and Colorado IPF consortiums, reported a novel association signal near the A-kinase anchoring protein 13 (AKAP13; rs62025270) [26]. The A allele that is associate with increased susceptibility to IPF was also associated with increased expression of AKAP13 mRNA in lung alveolar epithelium and lymphoid follicles from patients with IPF. AKAP13 interacts with protein kinase A and the Rho/Rac family of guanosine triphosphate binding proteins, which raises the possibility that targeting the RhoA pathway inhibitors may be beneficial in patients with IPF.
●Kinesin family member 15 – Whole genome sequencing of 1725 patients with familial or sporadic IPF and 23,509 nondiseased controls demonstrated an excess number of rare deleterious variants of kinesin family member 15 (KIF15), with similar findings in independent replication cohorts [45]. In this study, the single-nucleotide polymorphism with the most significant association (rs74341405) had an allele frequency of approximately 6 to 7 percent in IPF patients and 4 percent in healthy controls. KIF15 is involved with spindle separation during mitosis and is expressed in replicating lung epithelial cells, macrophages, and T-cells. Both common and rare variants lead to reduced KIF15 expression and reduced rates of cell proliferation in vitro, while replicating epithelial cells of IPF patients demonstrate reduced KIF15 expression in vivo. These findings suggest that decreased epithelial replicative reserve may play a role in susceptibility to IPF.
Additional genetic variants — Genome-wide association studies using IPF cohorts have identified multiple additional associated loci including FAM13A (4q22), DSP (6p24), MAD1L1 (7p22), ZKSCAN1 (7q21-22), DEPTOR (8q24), OBFC1 (10q24), ATP11A (13q34), IVD and KNL1 (15q15), IL9RP3 (16p13), DPP9 (19p13), TOLLIP (11p15), MDGA2 (14q21), SPPL2C (17q21), and STMN3 (20q13), as well as chromosomal regions 7q22, 10q25, and 15q14-15 [26-28,46].
One group used data from a large GWAS derived from three individual studies (2700 cases and 8600 controls [47]) to create a polygenic risk score (PRS) including thousands of common variant SNPs below genome-wide significance (but excluding MUC5B) [48]. In validation testing, those in the top quintile of the PRS had seven-fold higher odds of having IPF than those in the bottom quintile. Collectively, this PRS was estimated to explain a similar degree of genetic variance in those with European ancestry as the MUC5B promoter polymorphism alone (4 to 14 percent versus 2 to 11 percent, respectively) and offered similar prediction characteristics for IPF in this population (area under curve 0.7 for PRS versus 0.73 for MUC5B). The polygenic risk score also demonstrated an ability to discriminate those with interstitial lung abnormalities who are likely to radiologically progress (OR 1.16, 95% CI 1.02-1.31), but these odds were very modest compared with the odds of progression based on the MUC5B promoter polymorphism (OR 2.6 and 2.8, in two prior studies [49,50]).
Susceptibility versus progression — The relationship between genetic variants associated with disease susceptibility versus disease progression is complex.
A genome-wide association study of nearly 2000 IPF patients focused on transplant-free survival, found no significant correlation between known susceptibility variants and survival. This suggests that there may not be a large overlap between genetic susceptibility and risk for progression [51].
In contrast, evaluation of individual variants in IPF cohorts has suggested that some genetic susceptibility variants can impact patient outcomes. For example, the MUC5B promoter polymorphism, while associated with disease risk, has also been linked with improved survival across multiple IPF cohorts [52]. In addition, certain TOLLIP genotypes have been associated with differences in survival in patients with IPF [27,53].
Several genes not associated with genetic susceptibility to IPF have been independently identified as contributors to disease progression or mortality.
●In one genome-wide association study, a variant intronic to the gene proprotein convertase subtilisin/kexin type 6 (PCSK6) was associated with differential transplant free survival in two IPF cohorts comprising nearly 2000 patients [51].
Mechanistically, PCSK6 is a widely expressed mediator of transforming growth factor beta (TGF-beta) processing; altering expression of the gene has been found to lead to changes in collagen deposition, TGF-beta activation, and extracellular matrix formation [54]. PCSK6 levels in the lung and blood were negatively correlated with transplant-free survival across independent IPF cohorts, supporting a biologic role for PCSK6 in IPF progression [51]. However, the variant found in the genome-wide association study is too rare (~1 percent prevalence) to explain variation in PCSK6 levels seen in the IPF patient samples.
●Another genome-wide association study of 1329 individuals of European ancestry from four IPF cohorts identified a single genetic variant associated with disease progression, as assessed by FVC decline [55]. This variant, located in an intron of the antisense RNA gene for protein kinase N2 (PKN2-AS1 [1p22]), was associated with a 140 mL/year/variant decline in FVC (95% CI -180 to -100 mL). There was no association with baseline lung function or with response to nintedanib, pirfenidone, or antimicrobial therapy.
Interestingly, PKN2 has been linked to fibrotic processes and to TGF-beta signaling through interactions with Ras-homolog family member A (RhoA). The variant allele was not associated with decreased survival in this cohort, but the study may have been underpowered to assess that outcome.
●A genetic polymorphism in the toll-like receptor 3 (TLR3) has also been associated with disease progression in two IPF cohorts [56].
Inflammation — Multiple observations have raised the possibility that inflammation precedes the development of fibrosis during IPF pathogenesis:
●In many animal models of fibrosis, inflammation precedes the development of a fibrotic response, and suppression of the inflammatory alveolitis attenuates the subsequent fibrotic response [57].
●Histologically, the alveolitis of early pulmonary fibrosis in animal models is dominated by inflammatory cells, including alveolar macrophages, neutrophils, eosinophils, and lymphocytes. Increased numbers of basophils and mast cells also have been described [58].
●Asymptomatic relatives of patients with a familial form of IPF can have cellular evidence of alveolitis in the absence of clinically recognizable disease [59].
The alveolar macrophage has been proposed to play a pivotal role in the inflammatory pathogenesis of IPF due to its ability to secrete proinflammatory and profibrotic cytokines that affect mesenchymal cell proliferation and promote collagen deposition [3,9].
However, the idea that lung inflammation is necessary to produce fibrosis in IPF is disputed for several reasons [60]:
●Inflammation is generally minimal in patients with IPF, and there is no evidence that patients with early disease have more prominent inflammatory changes [1,5].
●Fibrosis can be induced in laboratory animals in the absence of inflammation [8].
●Anti-inflammatory therapy with systemic glucocorticoids has failed to alter the natural history of IPF, and some anti-inflammatory regimens lead to clinical worsening. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Therapies without clear benefit'.)
Fibroblast and epithelial cell dysfunction — Another theory posits that IPF results from aberrant fibroblast and epithelial cell function and abnormal epithelial-mesenchymal interactions, with little or no inflammatory component [60]. This view is supported histologically by the presence of fibrotic foci directly beneath areas of damaged epithelium without the presence of a significant inflammatory cell infiltrate [61-63]. Initiation and perpetuation of this fibrotic response may depend upon genetic factors, environmental triggers, and imbalance of oxidants and antioxidants; imbalance of Th1 and Th2 cell-derived cytokines may also be important [64-67]. (See 'Mechanisms of fibrosis' below.)
PERPETUATION — A critical element in the pathogenesis of idiopathic pulmonary fibrosis (IPF) is the unremitting fibrotic response; many patients with IPF have moderate to advanced fibrotic disease at the time of diagnosis without histologic evidence of cellular inflammation in the pulmonary parenchyma. This differs from inflammatory pulmonary conditions such as bacterial pneumonia, in which massive pulmonary inflammation is followed by recovery with minimal long-term effects on lung structure and function. The stimulus that promotes pulmonary fibrosis instead of effective repair is unknown. If inflammation is an important component of IPF pathogenesis, the mechanisms involved in the clearance of acute inflammation may be impaired [65,66,68].
In some animal models of pulmonary fibrosis, inflammation is followed by recovery, and fibrosis does not progress. For example, following intratracheal instillation of the fifth component of complement, there is a massive influx of neutrophils and monocytes within 24 hours [66]. Similarly, intratracheal instillation of the anti-neoplastic antibiotic, bleomycin, leads to an initial injury to the alveolar epithelium and an influx of activated macrophages and neutrophils into alveoli that resolves in two to four weeks [66,68,69]. However, monocytes persist in alveolar walls up to eight weeks after exposure, at which time the histology is predominantly fibrotic [66].
PROGRESSION — Another characteristic feature of idiopathic pulmonary fibrosis (IPF) is that the fibrotic process is progressive. Once initiated at the epithelial barrier of the alveoli, the injury to epithelial cells and basement membrane results in complex cell and cytokine interactions that extend the fibrotic process to involve the alveolar walls, alveolar lumen, and then adjacent areas of lung parenchyma.
An early consequence of injury to the epithelium is development of an intraalveolar exudate. Organization of the intraalveolar exudate leads to alveolar collapse with apposition of the denuded alveolar walls and loss of surfactant [70].
Both epithelial and basement membrane injury appear necessary for the development of intraluminal fibrosis. In the normal lung, the alveolar epithelium is comprised predominantly of type I epithelial cells, with a relatively small number of type II epithelial cells [71]. Following injury, type II cells proliferate and differentiate into type I cells, and are normally responsible for reepithelialization of injured alveoli [72].
In IPF, loss of epithelial type I cells and marked proliferation of epithelial type II cells are noted; however, these cells do not appear to reepithelialize the alveolar space in IPF [73]. This may be due to continued abnormalities of the basement membrane, which has microscopic alterations including duplication and fragmentation [70]. These basement membrane abnormalities in turn permit the migration of mesenchymal cells from the interstitium to the alveolar regions of the injured lung [62]. Excessive deposition of collagen by mesenchymal cells appears to prevent reexpansion of the collapsed airspace. The pattern of these changes suggests that chronic or recurrent injury to the alveolar epithelium may result in the progressive nature of intraalveolar exudates, fibrosis, and remodeling.
It is also possible that an initial injury and release of cytokines leads to long-lasting effects on fibroblasts. For example, in an experimental model of IPF, the release of transforming growth factor-beta1 (TGF-beta1) from alveolar epithelial cells for four days led to induction of fibroblast growth factor (FGF)-2, which was sequestered in the fibroblast matrix and led to an altered fibroblast phenotype with continued proliferation long after the exposure to TGF-beta1 [74].
In patients with IPF, serum concentrations of lung surfactant proteins (SP-A and SP-D) and Kerbs von Lungren 6 antigen (KL-6) are increased, and changes in serum concentration of KL-6 may be a marker for disease activity [75,76]. Lysyl oxidase-like 2 (LOXL2), which promotes collagen cross-linking, is detectable in serum from IPF patients and is associated with disease progression [77].
MECHANISMS OF FIBROSIS — The mechanism of fibrosis in idiopathic pulmonary fibrosis (IPF) remains elusive; however, a number of likely contributors have been identified (figure 1). It is possible that multiple microinjuries to alveolar epithelial cells induce a fibrotic environment, and that growth factors secreted by the injured epithelial cells recruit fibroblasts that differentiate into myofibroblasts. Myofibroblasts are cells that express features of both fibroblasts and smooth muscle cells, and are identified by their expression of alpha-smooth muscle actin (SMA) [73]. After being recruited to the lungs or differentiated from resident fibroblasts, myofibroblasts secrete collagen, which accumulates due to imbalance between interstitial collagenases and their tissue inhibitors [60].
While recurrent microinjuries to the alveolar wall and distal airways seem to be necessary for the initiation of fibrosis, specific extrinsic factors that might contribute to epithelial injury have yet to be fully elucidated. Since almost 90 percent of patients with IPF have physiologically detectable gastroesophageal reflux, often in the absence of symptoms [78], it is conceivable that microaspiration of acid into the distal lungs could be one cause of recurrent insults to epithelial barrier, altered epithelial-mesenchymal interactions, and subsequent fibrosis in genetically predisposed individuals. Further studies are required to determine if a causal relationship exists between gastroesophageal reflux and IPF.
Altered reepithelialization — A considerable body of evidence suggests a critical role for alveolar epithelial cells (AEC) in the pathogenesis of IPF [63,79]. Electron microscope studies demonstrate that resident mesenchymal cells are located in the space between the alveolar epithelium and the capillary endothelium [80]. The close proximity of mesenchymal cells to epithelial cells may contribute to the regulation of cell proliferation and connective tissue synthesis by fibrogenic cytokines released from epithelial cells. The current hypothesis suggests that repeated subclinical injury to the lung injures the alveolar epithelial, the subepithelial, and adjacent endothelial basement membranes [63]. This injury permits entry into the alveoli of cells of the mesenchymal lineage, and also other cells and cytokines. Eventually, based on a complex integrated process that is poorly understood, there is the emergence of a phenotype of fibroblasts that are highly active, proliferative and contractile.
In IPF, there is loss of type I epithelial cells and proliferation of type II cells; orderly reepithelialization followed by differentiation of the type II cells to type I AECs does not occur [72]. This lack of normal reepithelialization may, in part, be due to an aberrant activation of the Wnt signaling pathway following to lung injury [80]. The Wnt proteins inhibit phosphorylation of beta-catenin by glycogen synthase kinase 3b (GSK3b), and prevent its translocation to nucleus and activation of the lymphoid enhancing factor/T-cell factor (LEF/TCF) transcription factors; this is believed to activate proliferation of type II cells and inhibit their differentiation, with eventual triggering of divergent epithelial regeneration at bronchoalveolar junctions and possibly leading to epithelial-mesenchymal transformation [81].
Another possible abnormality of the alveolar epithelium in IPF patients is impaired regenerative capacity of the epithelium. In some IPF patients the impaired regeneration could be genetic or age-related. For example, in a cohort of familial IPF patients there is dysfunctional telomerase shortening, which may lead to cellular senescence and poor reepithelialization, either after an injury or after natural cell turn-over. (See 'Genetic predisposition' above.) It then follows that IPF patients maybe a subset of genetically susceptible individuals, in whom epithelial regeneration may become impaired with advancing age [82]. This speculation fits with observation of increase in incidence and prevalence of IPF with advancing age [82]. Another well recognized aberrancy of the AEC in IPF patients may be the overproduction and release of fibrogenic cytokines and growth factors.
Cytokines, growth factors, and other molecules — While the exact nature of the initiating injury and the subsequent cascade of mechanistic events needs to be elucidated, it is now clear that the interaction of growth factors, cytokines, and other mediators with cells resident in the lung is important to the evolution of the fibrotic response in IPF (figure 1) [83-86]. Resident epithelial cells, fibroblasts, and endothelial cells within the lung produce an array of cytokines and growth factors that stimulate fibroblast proliferation and matrix synthesis. Following epithelial injury, fibrosis is believed to progress due to an imbalance between many groups of molecules that include proinflammatory and antiinflammatory cytokines, fibrogenic and antifibrogenic polypeptides, oxidants-antioxidants, and angiogenic and angiostatic molecules [84,87].
Unlike bronchoalveolar lavage (BAL) from normal controls, BAL from patients with IPF contains increased amounts of transforming growth factor-beta (TGF-beta), including the active form TGF-beta1 [88,89]. TGF-beta1 is one of the most potent regulators of connective tissue synthesis due to its ability to increase connective tissue synthesis, down-regulate connective tissue proteases, and increase the inhibitors of connective tissue proteases [88,90]. TGF-beta1 can also induce a number of growth factors and cytokines that participate in fibrosis, including connective tissue growth factor (CTGF), fibroblast growth factor (FGF-2), platelet derived growth factor (PDGF), insulin-like growth factor (IGF), and interleukins (ILs) [84,91]. The role of TGF-beta in IPF is supported by inhibition of fibrosis in experimental animals by reducing its expression, signaling, and activity.
CTGF is a downstream mediator of TGF-beta1; it influences connective tissue synthesis by fibroblasts and functions as a mitogen for cells independently or in association with other mediators. CTGF expression is increased in BAL of patients with IPF [91,92].
Another cytokine implicated in IPF is tumor necrosis factor-alpha (TNF-alpha). TNF-alpha expression is increased in IPF, but its specific role is not clear. TNF-alpha has the ability to increase production of TGF-beta1 and other peptide mediators, stimulate fibroblast proliferation, and induce collagen synthesis [93,94]. In mice with established fibrosis, TNF-alpha reduced the fibrotic burden and improved lung function [95]. Among individuals with TNF-alpha gene polymorphisms, there is an increased risk of developing IPF [96].
In contrast, expression of interferon-gamma (IFN-gamma), an inhibitor of fibroblast proliferation and connective tissue synthesis, appears to be deficient in lungs from patients with IPF [97-100]. IFN-gamma also suppresses the Th2-type inflammatory response. While these observations suggested a potential therapeutic role for IFN-gamma, treatment with subcutaneous humanized interferon gamma-1b did not reduce mortality among patients with IPF [101].
In IPF, there is also an overexpression of fibrotic cytokines. The putative role of chemokines such as monocyte chemoattractant protein 1 (MCP-1) in the recruitment of IPF cells is becoming increasingly recognized. TGF-beta, CTGF, IL-4, IL-13, FGF-2, IGF-1, PDGF and GM-CSF are fibrogenic and IFN-gamma, IL-1, IL-10, IL-12, IL-17 are anti-fibrogenic molecules. Evolution of fibrosis appears to involve the activator protein (AP)-1 transcription factor and the fos-related protein Fra-2 [102].
Additional proteins that may contribute to pathogenesis or reflect disease activity of IPF have been identified using gene expression profiles [103-108]. As an example, genes over expressed in lung tissue and blood from patients with IPF include matrix metalloprotein (MMP)-7, MMP-1, surfactant protein A1, cyclin A2 (CCNA2), and alpha-defensins [105-107]. Comparing gene expression profiles from IPF lungs with profiles of genes associated with lung development may provide insight into the pathogenic mechanisms [103,104]. Furthermore, a signature of increased MMP-7 and MMP-1 has been noted in the peripheral blood of patients with IPF and levels of these proteins may correlate with disease activity [108].
Fibrotic foci — Fibrotic foci are now recognized as the characteristic histological feature of usual interstitial pneumonia (UIP) (picture 1) [1,6]. Following the induction of fibroblast activity by epithelial injury, fibroblasts and myofibroblasts appear to organize into fibrotic foci that precede the appearance of end-stage fibrosis [61]. These fibroblast foci are situated adjacent to sites of epithelial cell and basement membrane damage and consist of aggregates of actively proliferating fibroblasts and myofibroblasts.
The persistence of fibroblasts and formation of fibroblast foci may be regulated by inhibition of apoptosis of fibroblasts. For example, IL-4 has been shown to induce macrophage derived insulin-like growth factor-1 (IGF-1) and inhibit IPF fibroblast apoptosis [109]. In another study, pigment epithelium-derived factor (PEDF), a 50 kDa protein, was expressed in fibroblasts of IPF lungs, indicating its possible role in apoptosis and maintenance of fibroblasts [110]. These cells also express different intermediate filaments than fibroblasts; however, the pattern of expression varies in different tissues and under different pathological conditions.
Fibroblasts differentiate into myofibroblasts under the influence of transforming growth factor beta (TGF-beta), which results in expression of alpha smooth muscle actin (SMA), increased collagen production, and decreased synthesis of tissue inhibitor of metalloproteinase 2 (TIMP-2) [111-113]. Fibrotic foci can be identified by the presence of proliferating myofibroblasts that are actively synthesizing collagen [3,111].
Soluble mediators secreted by alveolar epithelial cells and other cells in the surrounding milieu are believed to induce leukocyte influx, stimulate fibroblast activity, and promote fibrosis. Important among these are TGF-beta, TNF-alpha, and IL-8. TGF-beta is produced by activated epithelial cells, macrophages, and endothelial cells, and is the most crucial mediator in the development of pulmonary fibrosis [88,90]. It is elevated both in patients with IPF and following intratracheal instillation of bleomycin in the murine model of IPF. In addition, fibrosis is attenuated by the inhibition of TGF-beta [114,115]. Specific polymorphisms of the gene encoding TGF-beta appear to increase the risk of disease progression [116].
Mesenchymal cells — The mesenchymal cell population at the site of fibrotic foci (picture 1) includes fibroblasts, myofibroblasts, pericytes, smooth muscle cells, and undifferentiated cells [117].
●The fibroblasts at these foci could be derived from four sources: interstitial peribronchiolar and perivascular adventitial fibroblasts, epithelial cells, circulating fibrocytes, and bone marrow-derived marrow stem cells [118]. These cells are located predominantly within alveolar walls.
●Myofibroblasts, which are present in wound granulation tissue and have morphologic features of both fibroblasts and smooth muscle cells, are derived from fibroblasts and epithelial cells. (See 'Myofibroblasts' below.)
●Smooth muscle cells are located within the walls of the airways and blood vessels.
●Pericytes are distributed along the pulmonary capillaries. Mouse models suggest pericytes are an important myofibroblast precursor however, their role in human IPF is not known [119].
●Contractile interstitial cells (CICs) are located predominantly within the alveolar walls and share ultrastructural features with myofibroblasts. They are abundant in the normal lung. One study using ultrastructural morphometry found that CICs account for 42 percent of the interstitial lung volume and comprise 18 percent of all lung parenchymal cells [120].
These same populations of cells are present in patients with IPF, but their proportion is greater than in the normal lung. As an example, one study found that IPF lungs demonstrated a 1.8-fold increase in the proportion of parenchymal cells that were mesenchymal in origin, and that these cells proliferated at a faster rate in the IPF lung than in the normal lung. These alterations were most pronounced in the fibroblast populations with altered phenotypes [109,111,112].
Fibroblast subtypes — IPF is characterized by fibroblast subpopulations that differ in their behavior when compared to fibroblasts isolated from normal lungs. These differences include altered proliferative potential, distinctive gene and cell surface marker expression, and dissimilar cell-mediated responses [67]. Whether these differences occur as a primary phenomenon or are secondary to prolonged exposure to an inflammatory milieu is presently unclear. It appears that these changes are important in transforming the fibroblast from a relatively passive cell into an important factor in the pathogenesis of IPF [121]. Regardless of the phenotypic differences, the fibroblast-like cell is the key target-effector cell that appears to determine the fibrotic response in IPF [117].
Beyond identification of distinct lung mesenchymal cell populations based upon expression of protein microfilaments, lung fibroblast subsets have been separated according to their expression of membrane proteins. Two examples of such cell surface protein markers, which show distinct differences in proliferation rate, collagen deposition and morphology, are the thymocyte 1 antigen (Thy 1) and the complement 1q (C1q) receptor [122-124].
C1q receptor subtypes — Cell culture media conditions can be manipulated to enhance the growth of normal human lung-derived fibroblast cell populations with varying C1q binding affinity. High and low fluorescence (HF and LF, respectively) anti-C1q antibody binding populations were sorted using FACS, and these cells maintained their respective fluorescent phenotypes after subculture [123].
A variety of behavioral differences among these subtypes have been noted in the past. These include differences in proliferation potential and type I collagen mRNA expression both under steady state conditions, and in response to TGF-beta 1 and IFN-gamma. Other studies have shown that a 51 kDa protein that binds the C1q-globular domain is found mostly in the HF cells. In contrast, the receptor for the C1q-collagen domain is produced largely by the LF fibroblasts [125]. These studies supported the concept that lung fibroblast subtypes have varying rates of proliferation and collagen synthesis, and that these population differences may have relevance to the pathogenesis of fibroproliferative lung disease in general.
More definitive evidence that fibroblast subtypes were since identified at the gene level was obtained by the isolation of mRNA, which is expressed at high levels in HF fibroblasts, and only marginally in LF cells [126]. This mRNA, called LR8, was not detected in cultures of other cell types. The expression of LR8 appears to be upregulated in human IPF lungs and mouse lungs with bleomycin-induced fibrosis [126].
Circulating fibrocytes — Fibrocytes found in the circulation are hematopoietic in origin [127,128]. These comprise 0.1 to 0.5 percent of circulating leukocyte population and are defined by expression of type I collagen (Col1), CD11b, CD13, CD34, CR45RO, MHCII, and CD86. Circulating fibrocytes are believed to bind to CCR7 and CXCR4 receptors in injured lung tissue under the influence of chemokines CCL21 and CXC chemokine ligand 12 (CXCL12). When cultured, the fibrocytes express connective tissue proteins and can differentiate into myofibroblasts, suggesting that fibrocytes could differentiate into myofibroblasts in IPF [127,128].
Evidence for potential involvement of circulating fibrocytes in IPF includes induction of chemokines CCL21 and CXCL12 in bleomycin-induced pulmonary fibrosis [127]. As an example, influx of circulating fibrocytes (CD45+Col+CXCR4+) was demonstrated in the lungs of bleomycin-treated SCID mice; this influx could be partially inhibited by CXCL12 specific antibodies [127]. These fibrocytes contributed significantly to the increase in collagen synthesis seen in this model [127].
Circulating fibrocytes are normally alpha-SMA negative but become positive over time in culture; this capacity is increased by TGF-beta. The presence of cells expressing Col1, alpha-SMA, and CD34+ in bronchial mucosa of asthma patients supports the role of circulating fibrocytes in humans [129]. The role of the circulating fibrocyte in the pathogenesis of IPF is unclear. Further studies are needed to clarify their contribution and to determine if the number of circulating fibrocytes varies during different stages of IPF (eg, acute exacerbation of IPF, stable disease, progressive disease).
Fibroblast proliferation — Lung biopsies from patients with IPF show an increase in the number of fibroblasts. The increase is largely due to increased proliferation. Evidence for this comes from observations of fibroblasts derived from patients with IPF and studied in vitro. As examples:
●The most consistent, though not universal, characteristic observed in fibroblasts isolated from IPF lungs is their augmented ability to proliferate either in vivo or in vitro [117,130,131]. In addition, they are relatively resistant to the antiproliferative effect of prostaglandin E2 (PGE2), have a diminished capacity to synthesize PGE2, and do not upregulate their inducible cyclooxygenase activity in response to a variety of agonists [132,133].
●One study examined fibroblast cell lines isolated from normal controls, from patients during an early cellular stage of fibrosis, and from patients during a late stage of dense fibrosis [131]. Under standardized and serum-free culture conditions, 55 percent of the normal cells were cycling when cultured, compared to 85 percent of the cells from early-stage fibrosis and 31 percent from the late stage of fibrosis. These conflicting results regarding differences in the in vitro proliferative characteristics of fibroblasts from normal and fibrotic lungs may be related to the stage of the fibrotic process.
●Tritiated thymidine uptake, a reflection of DNA replication, has been found to be increased in acute interstitial pneumonia [134], suggesting that increases in fibroblast-like cell numbers in fibrotic lesions arise from proliferation of local mesenchymal cell populations. A time course study of paraffin-embedded lung tissue sections from rats exposed to bleomycin supports the role of local mesenchymal cell proliferation in the pathogenesis of fibroproliferative lung lesions [135].
Myofibroblasts — Myofibroblasts produce interstitial collagens in significantly greater amounts than fibroblast-like cells [73,111,136]. Two main sources of myofibroblasts in IPF have been identified. It is believed that fibroblasts differentiate into myofibroblasts under the influence of mediators, such as TGF-beta. In addition, a portion of fibroblasts may arise from mesenchymal transformation of local epithelial cells, as observed in a renal model of fibrosis [137,138].
Transdifferentiation of epithelial cells through epithelial mesenchymal transformation (EMT) is thought to be another source of myofibroblasts [138,139]. EMT is a form of metaplasia that has long been known to play a role during tumor progression. Growth factors promoting EMT include TGF-beta, epidermal growth factor (EGF), hepatocyte growth factor (HGF), and fibroblast growth factor (FGF); transcription factors Smads, Slug, Snail, Scatter, lymphoid enhancing factor-1, and beta-catenin are also involved [139,140]. In the process of EMT, cells acquire myofibroblast markers (eg, SMA), fibroblast markers (eg, FSP1), and lose epithelial markers (eg, E-cadherin, zonula occudents-1).
Myofibroblast apoptosis is a normal event during resolution of wound-repair, and failure of their apoptosis may also lead to accumulation of myofibroblasts and persistent production of extracellular matrix (ECM) [141]. In the rat model of bleomycin-induced lung fibrosis, both myofibroblast-like cells and fibroblasts were increased in number 14 days after the administration of bleomycin. However, at 28 days post exposure, fibroblast numbers returned to baseline values, while the number of myofibroblast-like cells increased 10-fold when compared to normal lung [136].
Another study reported that 7 and 14 days following bleomycin administration, rat lung specimens revealed an increase in two distinct mesenchymal cell populations [142]. One type of mesenchymal cell was located within areas of active fibrosis and demonstrated expression of alpha-SMA, desmin, and procollagen mRNA. The other was predominantly localized within fibrotic submesothelial areas and expressed only SMA and procollagen mRNA. Using colocalization of SMA and procollagen alpha1(I) mRNA expression, lung myofibroblasts were found to be responsible for the vast majority of collagen synthesis. A similar conclusion regarding the major role of the myofibroblast in collagen accumulation in human fibrotic lung disease was drawn from immunohistochemical analysis of lung biopsy specimens from patients with IPF, acute respiratory distress syndrome, and cryptogenic organizing pneumonia (formerly known as bronchiolitis obliterans organizing pneumonia) [143].
In a bleomycin-fibrosis model, overexpression of the gene hyaluronan synthase (produces the extracellular matrix component hyaluronan) and its cognate receptor CD44 promoted the conversion of myofibroblasts into an aggressive and invasive phenotype [144].
The contractile property of myofibroblasts has been demonstrated in vitro using strips of fibrotic lung that contract in response to epinephrine and other agents [111]. In addition, the increased proportion of myofibroblast-like cells correlated with greater contractile properties when cultured on collagen gels. Of note, the cells isolated from bleomycin-treated lung also expressed more mRNA for TGF-beta1, and reverted to the phenotype isolated from normal lung when treated with anti-TGF-beta antibodies [142]. As mentioned above, TGF-beta plays a significant role in the proliferation of the myofibroblast phenotype since it induces expression of SMA in lung fibroblasts in culture [145]. A temporal in vivo correlation also has been described between epithelial type II cell TGF-beta 1 expression and SMA expression in lung mesenchymal cells [120].
Using microRNA arrays on IPF lungs some interesting observations have been made. MicroRNAs (miRNAs) are short RNA molecules that contain approximately 22 nucleotides and function to inhibit or promote the degradation of specific target mRNAs. Aberrant expression of the microRNA family miR-21 has been demonstrated in myofibroblasts from IPF lungs, but not from normal controls. The miR-21 has been shown to function like an oncogene and in this manner prevents myofibroblast senescence and promotes proliferation and differentiation [146]. In contrast to miR-21, there is diminished expression of miR-29, which inhibits fibrogenic proteins; the diminished expression of miR-29 in IPF lung fibroblasts may result in excessive connective tissue synthesis [146]. Other microRNAs with profibrotic function (miR-145, miR-154, miR-199a-5p) or anti-fibrotic effects (miR-326, miR-17~92) are differentially expressed in IPF lungs [147-151]. Taken together these observations suggest that aberrant post-transcriptional gene regulation in fibroblasts of IPF patients may result in a unique phenotype of fibroblasts that proliferate excessively and synthesize connective tissue proteins without control.
COLLAGEN DEPOSITION — In idiopathic pulmonary fibrosis (IPF), excess collagen is produced by myofibroblasts and deposited in a disorganized manner within the extracellular matrix.
Normal lungs — Collagen is the predominant type of protein in the extracellular matrix of the lung, constituting 20 percent of the dry weight of normal lungs [152]. The collagen family of triple helical proteins includes approximately 28 variants, which are classified according to their gene structure and alpha chain composition into "fibril-forming," "fibril associated collagens with interrupted triple helix (FACIT)," "network forming," and "transmembrane" groups [153,154].
Normal lung collagen is composed of several different collagen types that are distributed in a cell and location specific manner, including [152]:
●Types I and III are the predominant isoforms and constitute >90 percent of the total lung collagen. These isoforms are mostly located in the interstitium, within the alveolar wall, and in association with the large bronchi and blood vessels.
●Type II is present in the cartilage of the central airways.
●Type IV is present in basement membranes.
●Type VI is present in the interstitium.
Biosynthesis of collagens involves several biochemical events [155]. Following DNA transcription, collagen mRNA is translated into procollagen alpha chains, which are then modified by the hydroxylation of proline and lysine residues. The pro-alpha chains are subsequently glycosylated and disulfide bonds formed, and then the chains are assembled into the triple helix characteristic of mature collagen. Lysyl oxidase-like 2 (LOXL2), which promotes cross-linking of collagen, is increased in serum samples from patients with IPF and may contribute to disease progression [77,156]. Finally, these collagen molecules are proteolytically cleaved to form fibrillar collagens [155].
In normal lungs, collagen is produced and degraded continuously; this process is tightly regulated to preserve the normal lung structure. Lung fibroblasts synthesize type I and II collagens and may degrade as much as 40 percent of all newly synthesized collagen [157,158]. The initial degradation process is accomplished intracellularly, and may take less than 15 minutes [152].
Collagen is also degraded extracellularly by a family of matrix metalloproteinases (MMPs) that includes collagenases [159]. Fibroblasts, epithelial cells, neutrophils, and macrophages all secrete these MMPs. The final amount of collagen that is deposited in the lung results from the balance between the processes of synthesis and degradation.
Idiopathic pulmonary fibrosis — In lungs from patients with IPF, excess collagen is deposited in the extracellular matrix; collagen type I predominates in areas of mature fibrosis, while collagen type III is the predominant type in areas of early fibrosis [62,155,160-162].
Immunostaining and in situ hybridization techniques have demonstrated an increased number of collagen-synthesizing fibroblasts in the lungs of patients with IPF [61,62,90]. These fibroblasts, found in clusters, form the characteristic fibrotic foci located in the subepithelial areas of injured lung. These foci are surrounded by residual areas of basal lamina, indicating that they are located on the airspace side of the injured alveoli. In lungs of patients with IPF, but not in normal controls, these sites contain fibroblasts synthesizing collagen [161].
Conflicting data have been obtained regarding the source of increased collagen deposition in pulmonary fibrosis. Increased numbers of collagen-synthesizing cells and increased collagen production have been noted in lung biopsies from patients with IPF [162]. However, fibroblasts isolated from the lungs of patients with IPF and systemic sclerosis were found to synthesize a similar amount of collagen compared with control cell lines, although the rate of collagen degradation was less [163,164]. Observations evaluating the expression of collagen type I and procollagen type I mRNA using in situ hybridization have helped to reconcile these observations, demonstrating increased expression of type I collagen within fibroblast foci, without evidence of increased type I procollagen mRNA expression in other areas [90]. Therefore, it appears that the widely variable collagen secretion observed in IPF could be due to a focal, rather than a generalized, increase in fibroblast activation.
In addition to increased synthesis and deposition of collagen, decreased collagenolytic activity could theoretically contribute to excess collagen deposition in IPF [165]. By analogy, human gingival fibroblasts isolated from fibrotic lesions appear to have a decreased phagocytic activity (for collagen) compared with those isolated from normal gingiva [166]. However, enhanced collagenase activity has been reported in other fibrotic lung diseases such as sarcoidosis [152]. Further studies are necessary to clarify the role of collagen degradation in the pathogenesis of IPF.
Future studies are warranted to investigate the potential of using biomarkers of collagen or collagen metabolism, reflecting the knowledge about collagen subtypes and other proteins or the synthesis and degradation of these proteins in patients with IPF.
IMPLICATIONS FOR PROGNOSIS — The definitions of IPF and usual interstitial pneumonia (UIP), as well as the classification of other idiopathic interstitial pneumonias (IIPs), have been clarified by international experts in Consensus Statements published by the Joint American Thoracic Society and European Respiratory Society [167]. Using this framework, pulmonary pathologists, radiologists, and physicians have improved their ability to classify distinct IIPs accurately, based upon both histological and clinical grounds. IPF can now be diagnosed with greater accuracy and can be more effectively separated from other IIPs. (See "Idiopathic interstitial pneumonias: Classification and pathology".)
In addition, increasing effort has focused on histopathologic subclassification of IPF, and the potential implications of these subclasses with respect to patient survival [4,6,168,169]. As an example, it is possible to perform detailed scoring of individual histopathologic features and correlate the results with outcomes [170]. In some (but not all) series, a high profusion of fibroblastic foci has been a marker for an increased risk of subsequent mortality [170-173]. A higher number of fibroblastic foci has also been associated with a decline in forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO) over 6 and 12 months of follow-up [172]. However, the utility of detailed scoring systems in the clinical management of patients with IPF has not been evaluated [172,174].
IMPLICATIONS FOR TREATMENT — Idiopathic pulmonary fibrosis (IPF) is now best conceptualized as a predominantly fibrotic disease that likely results from recurrent injury to the alveolar epithelium; once initiated, the abnormal fibrotic response to injury extends from the epithelium to the interstitial space. The identity and nature of the stimuli that trigger the initiating process in IPF are not understood, and in most cases cannot be recognized because patients generally seek help after the onset of symptoms, when the fibrotic process is already well established.
This inability to identify the initiating inflammatory process in human IPF (if there is one) may explain the failure of traditional antiinflammatory modalities, such as glucocorticoids and immunosuppressive agents [1,175-177]. As noted above, there is usually little or no evidence of inflammation at the time of diagnosis, which is when these agents have been used. As a result, it is not surprising that treatment with antiinflammatory and immunosuppressive agents has been largely ineffective. In addition, patients with IPF and short leukocyte telomere lengths have more frequent adverse outcomes with use of immunosuppressive therapy [178]. Monotherapy with N-acetylcysteine, a glutathione precursor and antioxidant, failed to decrease the rate of disease progression in IPF [179]. However, a clinical trial is underway to assess the efficacy of N-acetylcysteine in patients with IPF and a specific TOLLIP genotype (NCT#04300920) [53,180]. (See 'Additional genetic variants' above and "Treatment of idiopathic pulmonary fibrosis".)
With increasing recognition of the pathogenic role of fibroblast proliferation and fibrotic foci, treatment strategies have shifted towards antifibrotic agents. The rationale for the use of these agents rests upon the large amount of basic science data demonstrating an imbalance of cytokines, increased fibroblast proliferation, and excessive extracellular matrix deposition in the lungs of IPF patients. After clinical trials documented positive results in patients with IPF treated with nintedanib, an intracellular inhibitor of tyrosine kinases, this medication has now been approved for treatment in IPF [181,182]. Pirfenidone is another antifibrotic medication approved for use in IPF [183]. In contrast, simtuzumab, a monoclonal antibody against lysyl oxidase-like 2 (LOXL2) that inhibits collagen crosslinking, did not yield clinically measurable beneficial effects in patients with IPF [184]. Administration of epigallocatechin gallate (EGCG), an inhibitor of LOXL2 and TGFB-1/2, resulted in a reduction in profibrotic biomarkers in a small cohort of patients with pulmonary fibrosis, and further studies are planned to assess the safety of EGCG in IPF [185]. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Medical therapies'.)
Several other potential antifibrotic agents that had promising results in phase 2 trials have failed to confirm the results in phase 3 trials. These include: Pamrevlumab, a monoclonal antibody that targets connective tissue growth factor (CTGF) [186]; recombinant human pentraxin-2, a protein that inhibits differentiation of monocytes into proinflammatory macrophages and profibrotic fibrocytes [187]; and ziritaxestat, a novel autotaxin inhibitor [188].
Disordered coagulation and fibrinolysis may also be important in the pathogenesis of IPF and acute exacerbations of IPF, although in a clinical trial, warfarin was found to be harmful for patients with IPF [189] and the effectiveness of other anticoagulation therapies remains unclear [190,191].
Attention is also being directed at ways to prevent lung injury and thereby prevent further fibrosis. One hypothesis is that abnormal gastroesophageal reflux (GER) may contribute to lung injury and that prevention of microaspiration through adequate control of reflux may decrease the rate of progression of fibrosis. In this regard, there is increasing evidence to support this concept [192]. A prospective study documented a significantly decreased rate of disease progression with anti-acid treatment in patients with well-defined IPF participating in three clinical trials [193]. While a retrospective study suggested a better survival in IPF patients subjected to surgical intervention for control of GER [194], further research is needed to evaluate this hypothesis [195].
Given the multiple and complex mechanisms resulting in IPF, it is likely that multi-agent therapy and possibly pharmacogenetic approaches will be needed to obtain disease control.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topic (see "Patient education: Idiopathic pulmonary fibrosis (The Basics)")
SUMMARY
●Idiopathic pulmonary fibrosis (IPF), previously known as cryptogenic fibrosing alveolitis (CFA) in Europe, is a chronic, progressive fibrotic disorder of the lower respiratory tract that typically affects adults over age 40. (See 'Introduction' above.)
●While the specific cause of IPF is unknown, certain risk factors are associated with IPF, including genetic predisposition, cigarette smoking, environmental pollutants, and possibly chronic microaspiration. (See 'Initiation' above.)
●Several gene variants have been identified in patients with familial pulmonary fibrosis, including variants in genes associated with surfactant proteins, gel-forming mucin, and maintenance of telomere length. A number of variants have also been identified in individuals with sporadic IPF, suggesting a possible genetic predisposition to sporadic IPF. (See 'Genetic predisposition' above.)
●It is unclear whether inflammation (which resolves prior to clinical presentation of the patient) is the inciting stimulus in IPF, or whether aberrant epithelial cell and fibroblast responses to nonspecific injury cause the fibrotic response in the absence of inflammation. (See 'Initiation' above.)
●The mechanism of progressive fibrosis in IPF remains elusive; however a number of likely contributors have been identified (figure 1). It is possible that multiple microinjuries to alveolar epithelial cells induce a fibrotic environment, and that growth factors secreted by the injured epithelial cells activate and recruit fibroblasts. (See 'Mechanisms of fibrosis' above.)
●Following the induction of fibroblast activation, proliferation and differentiation by epithelial injury, fibroblasts and myofibroblasts organize into fibrotic foci; the appearance of fibrotic foci precedes the development of end-stage fibrosis. The evolution of this process is mediated by a variety of growth factors. (See 'Mechanisms of fibrosis' above.)
●In IPF, excess collagen is deposited in the extracellular matrix around fibrotic foci by fibroblasts and myofibroblasts. Collagen type III is the predominant form of collagen in areas of early fibrosis, while collagen type I predominates in areas of mature fibrosis. (See 'Collagen deposition' above.)
●Two antifibrotic agents, pirfenidone and nintedanib, have documented decreased rate of disease progression and are now in clinical use as approved treatment for IPF. Since several pathways are likely to be contributing to the pathogenesis of pulmonary fibrosis, effective therapy may require a combination of therapeutic strategies. Potential preventive measures that will decrease or halt progression of fibrosis need to be explored. (See 'Implications for treatment' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges A Narayanan, PhD, Nasreen Khalil, MD, and Carmen Mikacenic, MD, who contributed to earlier versions of this topic review.
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