Abstract

Endoplasmic reticulum (ER) stress is associated with development and progression of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). ER stress was first implicated in the pathogenesis of IPF >15 years ago with the discovery of disease-causing mutations in surfactant protein C, which result in a misfolded gene product in type II alveolar epithelial cells (AECs). ER stress and the unfolded protein response (UPR) have been linked to lung fibrosis through regulation of AEC apoptosis, epithelial-mesenchymal transition, myofibroblast differentiation, and M2 macrophage polarization. Although progress has been made in understanding the causes and consequences of ER stress in IPF and a number of chronic fibrotic disorders, further studies are needed to identify key factors that induce ER stress in important cell types and define critical down-stream processes and effector molecules that mediate ER stress-related phenotypes. This review discusses potential causes of ER stress induction in the lungs and current evidence linking ER stress to fibrosis in the context of individual cell types: AECs, fibroblasts, and macrophages. As our understanding of the relationship between ER stress and lung fibrosis continues to evolve, future studies will examine new strategies to modulate UPR pathways for therapeutic benefit.

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