Molecular Understanding

• The current hypothesis for IPF pathogenesis involves a predisposition, an initiation event, and progression.⁷⁶
• Genetic factors are implicated in a patient’s predisposition to IPF^{66,83,84,150,151}
• Injury to the alveolar tissue is thought to initiate an aberrant wound healing response.⁷⁶
• Failure to turn off wound healing pathways may lead to disease progression.¹¹³

MOLECULAR UNDERSTANDING OF IPF 

What is the pathogenesis of IPF? The molecular cause(s) of IPF are not yet fully understood.

CURRENT MODEL OF IPF PATHOGENESIS 

The current model of IPF pathogenesis suggests multiple factors and pathways interact through various stages of disease development to produce the histopathologic and clinical features of IPF.⁷⁶

CURRENT HYPOTHESIS

• Predisposition: Predisposing triggers result in epithelial cell dysfunction, creating a susceptible lung epithelium.⁷⁶
• Initiation: Aberrant wound healing in response to lung injury initiates pathogenic changes.⁷⁷
• Progression: Disease progression occurs due to ongoing extracellular matrix deposition, accumulation of myofibroblasts, and aberrant tissue remodeling.⁷⁶

• This polymorphism has also been associated with increased MUC5B mRNA expression⁸⁴ 
• MUC5B has a role in host defense responses in the airways, although its role in IPF pathogenesis is not yet clear⁸⁶ 

Rare Variants

• Surfactant Genes^78-80
  • SFT PC 
  • SFTPA2 
• Telomere-Related Genes^81,82,87
  • TERT
  • TERC
  • DKC1

In familial cases of pulmonary fibrosis, the most likely mode of genetic transmission is autosomal dominant with variable penetrance.⁸⁸ 

A subset of families with IPF have dominant mutations in 1 of 2 surfactant proteins.

Surfactant protein C (SFTPC) and Surfactant protein A (SFTPA2) are produced by alveolar epithelial cell (AECs).^78-80

In patients with mutations in surfactant proteins, defects in protein folding induce endoplasmic reticulum (ER) stress, which leads to epithelial cell death.^78,89

Cases of familial pulmonary fibrosis have led to identification of rare variants in telomere-related proteins. In patients with telomerase mutations, the proliferative capacity of alveolar progenitor cells may be limited.^81,82

Telomere-Related Genes 

Rare Variants.^81,82,87

• TERT
• TERC1
• DKC1

Additional evidence indicates telomeres are involved in sporadic forms of IPF as well. Up to one-third of patients with short telomeres in peripheral blood mononuclear cells were diagnosed with IPF, suggesting that defects in telomere maintenance may underlie one path to lung fibrosis.^87,90,91 

• Select variations in toll interacting protein (TOLLIP) are associated with reduced susceptibility to IPF.⁸³
• One mutation in MUC5B may result in decreased mortality from IPF.⁸³ 
• A specific mutation in toll-like receptor 3 (TLR3) results in greater risk of mortality and accelerated forced vital capacity (FVC) decline.⁹² 

However, it is not clear whether these gene variants can be incorporated into prognostic models to affect the clinical care of patients.⁸³

Predisposition to developing IPF is also associated with particular polymorphisms.

• Oxidative stress contributes to epithelial injury and fibroblast differentiation^93-97
• Aging leads to alterations in epithelial repair through autophagy pathways and worsens several animal models of lung fibrosis^98-100
• Mechanical factors including stretch/stress injury alter epithelial cell phenotype and cytokine production^101-103

IPF may be initiated by an injury to the alveolar epithelium.

IPF may be caused by an inappropriate or overexuberant wound-healing response in response to AEC injury,¹⁰⁴ although the source of injury is generally unknown.⁷⁶

Injury to the alveolar epithelium causes death of AECs.

Alveolar injury results in the death of some AECs through apoptosis and other pathways, as well as a loss of epithelial integrity.^105,106

AECs play an essential role in pulmonary function.

Type I AECs:

• Comprise >90% of alveolar surface of lung^107-109
• Interface with pulmonary capillaries to provide a surface for gas exchange^107,108
• Are sensitive to damage^107-109

Type II AECs:

• Are responsible for secreting surfactant^108-110
• Act as progenitor cells for both Type I and II AECs^107-110
• Play a role in innate immunity^108,110

AECs appear to turn over most frequently in the peripheral lung during maintenance.¹¹¹

The association between this turnover concentration and the earliest radiographic changes in IPF suggests that IPF may be related to these epithelial repair mechanisms.^112,113

• In response to AEC death, multiple cell types of release cytokines and chemokines.¹¹³ AEC death initiates a profibrotic response that results in extracellular matrix deposition, increased cell.

migration, and the formation of a fibroblastic focus.¹¹³

• Surviving AECs, as well as activated platelets and inflammatory cells, release of a variety of cytokines and chemokines, including transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF)^{104,114,115,116,117}

TGF-β likely plays a role in lung fibrosis. Both in vitro and in vivo studies have suggested that overexpression of TGF-β can lead to lung fibrosis.^118-120 Clinical investigations have found increased levels of active TGF-β in the lungs of IPF patients.¹²¹

These factors activate wound healing and epithelial repair pathways.¹⁰⁴

• In response to these molecular signals — particularly TGF-β — epithelial cells initiate repair programs^104,119
• Surviving epithelial cells also alter their phenotypes in response to injury-induced procoagulant signals¹¹³ Localized production of TGF-β and PDGF also activate fibroblasts, which differentiate into myofibroblasts^118,122 

Other factors also contribute to fibroblast differentiation. This process appears to be mediated at least in part through activation of developmental pathways (e.g., Wnt/β-catenin axis,^123-125 Sonic hedgehog pathway¹²⁶) and altered microRNA expression.^127,128

These differentiated fibroblasts then secrete additional extracellular matrix as a part of the normal wound healing process.^129,104,118

Factors that signal fibroblasts to migrate to the injured region of the lung and deposit extracellular matrix include:

• Cytokines^130-132
• Chemokines¹³³
• Lipid-mediated chemotaxis and proliferation¹³⁴
• Possible recruitment of circulating fibrocytes¹³⁵

Recurrent or ongoing injury may lead to fibrosis instead of normal repair.

• Repeated cycles of injury and/or incomplete repair may lead to progressive scar formation, which results in clinically evident lung fibrosis over time.¹¹³

Progression is characterized by fibroblast differentiation and extracellular matrix (ECM) deposition and remodeling.⁷⁶

• Disease progression in IPF is mediated by repeated cycles of injury, ECM deposition, and abnormal tissue remodeling^76,104
• Repeated microinjury and aberrant wound healing response lead to clinically evident fibrosis over time¹¹³

After injury, the ECM gets remodeled by a variety of cells. Differentiated fibroblasts (i.e., myofibroblasts), epithelial cells, and macrophages produce a variety of matrix metalloproteinase (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) that work to remodel the ECM.^136-140

Myofibroblasts produce increased amounts of collagen and other extracellular matrix proteins.¹¹³

• Enhanced collagen production and matrix remodeling create a positive feedback cycle that alters gene expression patterns, leading to further myofibroblast differentiation and activation of TGF-B through stretch-mediated integrin signaling^141-143
• These actions then further increase matrix remodeling⁷⁶

Further epigenetic and transcriptional regulatory changes, along with alterations in microRNA expression, lead to large-scale alterations in cellular gene expression patterns, culminating in a profibrotic phenotype.^128,144-148

Over time, microscopic changes result in macroscopic disease. These processes result in macroscopic disease, including the gross architectural destruction and honeycomb-like cystic changes that characterize advanced IPF.¹⁴⁹