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.

Figure 1

Schematic representation of cellular and contextual abnormalities in pulmonary fibrogenesis (IPF fibroblastic focus). A: Fibrogenesis is initiated by injury to, infection of, or intrinsic abnormalities (eg, surfactant dysfunction mutations) within alveolar epihtelial cells. Capillary disruption results in deposition of fibrin-rich provisional matrix, into which fibroblasts (either resident interstitial fibroblasts, fibrocytes, or EMT-derived) migrate. Signals for perpetuation of fibrogenesis (eg, fibroblast proliferation, myofibroblastic differentiation, extracellular matrix remodeling) may arise from the altered epithelium, alternatively activated macrophages (AAM), composition and/or biomechanical properties of ECM, or the fibroblasts themselves, recapitulating developmental pathways and resulting in progression of fibrogenesis (B). Epigenetic alterations, such as DNA methylation or histone modifications, lead to silencing of fibrosis supressor (FS) genes, further promoting an apoptosis-resistant myofibroblast phenotype.