Mechanisms of Fibrosis in IPF

Abstract

Idiopathic pulmonary fibrosis (IPF) is a disorder characterized by progressive destruction of normal lung architecture and replacement with abundant matrix that stiffens the lung and leads to respiratory failure. The pathobiology of IPF is characterized by the presence of alveolar epithelial cell (AEC) injury and apoptosis, which is accompanied by progressive fibrosis. Thus, while inflammatory signaling may still play a role in IPF, the previous paradigm of an inflammation-driven disorder (alveolitis) has been supplanted by the concept of IPF as a disorder of AEC injury accompanied by a non-resolving wound-healing response. AEC injury and apoptosis result in disordered cross talk between the epithelial and mesenchymal compartments via aberrant cell behavior, profibrotic signaling, and loss of inhibitory homeostatic signals. These aberrant signals lead to disruption of the alveolar basement membrane, formation of a provisional matrix, and recruitment of mesenchymal cells to form the fibroblastic focus, which serves as the site of new matrix accumulation in IPF. Myofibroblast differentiation, matrix synthesis and deposition, and tissue remodeling occur in response to transforming growth factor-β(beta) (TGF-β) and other growth factors. This remodeling process yields a stiffened, fibrotic matrix that independently perpetuates the fibrotic process via activation of TGF-β signaling and myofibroblast differentiation.Despite this mechanistic understanding of the reparative process, the etiology for the lack of resolution in IPF compared to other responses to lung injury remains unknown. While an effective therapy for IPF remains elusive, approaches to therapy have begun to evolve toward targeted therapies directed at putative growth factors, receptors, and enzymes for which robust evidence now exists regarding their mechanistic involvement in matrix remodeling.KeywordsIdiopathic pulmonary fibrosisFibrosisAlveolar epithelial cellApoptosisTransforming growth factor-betaIntracellular signalingFibroblastExtracellular matrixInflammationAngiogenesisCoagulation cascade