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, which stiffens the lung and leads to respiratory failure. The pathobiology of IPF is characterized by the presence of alveolar epithelial cell injury and apoptosis, accompanied by a progressive fibrosis. Thus, while inflammatory signaling may play a role in IPF, the previous paradigm of an inflammation-driven disorder (alveolitis) has been supplanted by the concept of IPF as an aging-related disorder of alveolar epithelial cell (AEC) injury and dysfunction accompanied by a non-resolving wound-healing response. AEC injury in IPF is promoted by the interaction of underlying genetic susceptibility, exogenous exposures, and aging-related changes in cellular fitness and cell-stress responses. Injured AEC display features of endoplasmic reticulum (ER) stress, phenotypic change, mitochondrial dysfunction, and senescence. Dropout of AEC occurs due to increased apoptosis and deficient reepithelialization. Together, this aberrant biology results in disordered cross talk between the epithelial and mesenchymal compartment in the alveolar unit. In association with AEC injury, there is disruption of the normal 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. Aberrantly activated (myo)fibroblasts populate the foci and, in response to transforming growth factor-β (TGF-β) and other growth factors, along with age-related changes in senescent phenotype, mitochondrial homeostasis, and epigenetic alterations, promote ongoing matrix synthesis and tissue remodeling. The remodeling process yields a stiffened, fibrotic matrix that independently perpetuates the fibrotic process via activation of mechanosensitive signaling pathways that perpetuate dysregulation of cell phenotype and matrix remodeling. Despite this mechanistic understanding of the reparative process, a full understanding of why there is not a lack of resolution of the wound-healing response in IPF remains unknown.