Pathogenesis of idiopathic pulmonary fibrosis: review of recent findings

Abstract

Idiopathic pulmonary fibrosis (IPF) is likely to result from the interaction between environmental exposures, including cigarette smoke, and genetic predisposition. This review focuses on clues provided by recent genetic association studies and other selected data and hypotheses. In IPF, association with surfactant mutations has highlighted the importance of type II epithelial cells, while shortened telomeres in some patients suggest that accelerated aging may play a role in the pathogenesis of lung fibrosis, possibly by affecting the renewal/differentiation potential of epithelial cells. The finding that a common variant in mucin 5B predisposes individuals to both familial and sporadic IPF suggests a hitherto under-investigated role of bronchiolar cells and mucins. Although the pathogenetic link between mucins and lung fibrosis is not known, it is possible that MUC5B overexpression interferes with physiological mucosal host defense, with reduced clearance of micro-organisms or inorganic noxious agents, or induction of endoplasmic reticulum stress. Other components of innate and adaptive immunity are likely to be involved in IPF pathogenesis/progression. Finally, the importance of the clotting cascade in IPF pathogenesis has been confirmed by a recent epidemiological study, in which patients with IPF were almost five times more likely than general population controls to have at least one inherited or acquired clotting defect.

Lung Pericytes and Resident Fibroblasts

“…15,53,64 Fibrotic lung diseases are a growing and serious cause of morbidity and mortality with scant therapeutic options. 13,78,79 Pollutants, such as tobacco smoke or asbestos, autoimmune diseases, and inflammatory disorders, directly cause lung fibrosis. When injured, lung epithelial cells release a diverse and potent assortment of factors that can activate fibroblasts, including TGF-b, connective tissue growth factor, prostaglandin E 2 (PGE 2 ), sonic hedgehog (SHH), WNT1 inducible signaling pathway protein 1 (WISP1), and IL-1a.…”

“…82 A strengthening hypothesis to generally explain fibrotic lung diseases is that injury or infection overcomes an already stressed epithelium's capacity for recuperation and engages innate immune pathways that may circumstantially promote or protect from harm. 13,15,53,64,75,78,81 Myofibroblasts are the key effector cell type in fibrotic disease because they are dominant builders and remodelers of extracellular matrix that also exert strong force on their surroundings. 9,10,12e14,27,30,38,53,64,78,83 Myofibroblasts may be distinguished by expressing a-SMA and similar proteins in common with muscle, forming stress fibers, and by contractility.…”

“…21 TGF-b, connective tissue growth factor, ANGII, SHH, WISP1, and reactive oxygen species all mediate interactions between lung epithelium and fibroblasts, but these have been predominantly investigated as excessively induced drivers of fibrosis. 13,15,16,53,78 However, these factors are also part of beneficial and self-limited wound healing, and epithelial restoration after injury is widely proposed to be the key difference between maintaining or losing lung function. 13,75,78,82 PGE 2 is a notable exception because it seems deficient in disease.…”

“…13,15,16,53,78 However, these factors are also part of beneficial and self-limited wound healing, and epithelial restoration after injury is widely proposed to be the key difference between maintaining or losing lung function. 13,75,78,82 PGE 2 is a notable exception because it seems deficient in disease. Airway epithelial cells are capable of high PGE 2 output; PGE 2 suppresses fibroblast migration, proliferation, and myofibroblast differentiation; and PGE 2 levels are lower in IPF patients.…”

FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis

“…The etiology of IPF is poorly understood. The current concept involves repeated alveolar injuries of unclear nature, providing signals for fibroblast activation, proliferation, and differentiation to myofibroblasts (2)(3)(4)(5)(6). The latter overgrow the delicate alveolar lung tissue and secrete increased amounts of extracellular matrix (ECM) proteins.…”