Emerging Concepts in the Pathogenesis of Lung Fibrosis

Abstract

Fibrogenesis is an often-deadly process with increasing world-wide incidence and limited therapeutic options. Pulmonary fibrogenesis involves remodeling of the distal airspace and parenchyma of the lung, and is characterized by excessive extracellular matrix deposition and accumulation of apoptosis-resistant myofibroblasts. Recent studies have added significantly to our understanding of the complex mechanisms involved in lung fibrogenesis. Emerging concepts in this field include the critical role of the epithelium, particularly type II pneumocytes, in the initiation and perpetuation of fibrosis in response to either endogenous or exogenous stress; a growing awareness of alternative activation of macrophages in tissue remodeling; growing appreciation of the alternative origins and phenotypic plasticity of fibroblasts; the roles of epigenetic reprogramming and context-dependent signaling in profibrotic phenotype alterations; and recognition of the importance of cross talk and convergence of intracellular signaling pathways. In vitro, in vivo, and in silico approaches support a paradigm of "disordered re-development" of the lung. Designing effective antifibrotic interventions will require accurate understanding of the complex interactions among the genetic, environmental, epigenetic, biochemical, cellular, and contextual abnormalities that promote pulmonary fibrogenesis.

Constrictive Bronchiolitis in Cystic Fibrosis Adolescents with Refractory Pulmonary Decline

“…This is similar to that which we have reported in end-stage CF samples (11). Staining for a-SMA highlighted the presence of a TGFb-dependent myofibroblast phenotype that is known to be involved in fibrogenesis (12,26,27). In sections with mature fibrosis, specimens become less cellular, and collagen staining becomes more prominent.…”

All-transretinoic acid ameliorates bleomycin-induced lung fibrosis by downregulating the TGF-β1/Smad3 signaling pathway in rats

“…These data are in agreement with the notion that fibroblasts are the primary effectors of tissue fibrosis because fibroblasts produce collagen and other extracellular matrix proteins. 24 In lung fibrogenesis, fibroblasts often differentiate into myofibroblasts, which exhibit enhanced fibrotic, contractile, and migratory activities. 25 a-SMA is a marker of myofibroblasts and a primary contributor to the contractile force in myofibroblasts.…”

MiR-21 Mediates Fibrogenic Activation Of Pulmonary Fibroblasts And Lung Fibrosis

“…An important pathological feature of IPF is the presence of fibroblastic foci in the lungs, and the presence and extent of such fibroblastic foci is one of the most reliable markers of poor prognosis in patients with IPF (Wynn, 2007;Hardie et al, 2009). Fibroblastic foci are aggregations of fibroblasts/myofibroblasts that produce excessive ECM components (Wynn, 2007;Hardie et al, 2009). TGF-1 has been shown to be an important mediator of lung fibrosis and can induce differentiation of pulmonary fibroblasts into myofibroblasts characterized by -smooth muscle actin (-SMA) expression and active synthesis of ECM proteins (Lee et al, 2006;Cutroneo et al, 2007).…”