Involvement of Endoplasmic Reticulum Stress in Myofibroblastic Differentiation of Lung Fibroblasts

Abstract

Stress that impairs endoplasmic reticulum (ER) function leads to an accumulation of unfolded or misfolded proteins in the ER (ER stress) and triggers the unfolded protein response (UPR). Recent studies suggest that ER stress is involved in idiopathic pulmonary fibrosis (IPF). The present study was undertaken to determine the role of ER stress on myofibroblastic differentiation of fibroblasts. Fibroblasts in fibroblastic foci of IPF showed immunoreactivity for GRP78. To determine the role of ER stress on α-smooth muscle actin (α-SMA) and collagen type I expression in fibroblasts, mouse and human lung fibroblasts were treated with TGF-β1, and expression of ER stress-related proteins, α-SMA, and collagen type I was analyzed by Western blotting. TGF-β1 significantly increased expression of GRP78, XBP-1, and ATF6α, which was accompanied by increases in α-SMA and collagen type I expression in mouse and human fibroblasts. A chemical chaperone, 4-PBA, suppressed TGF-β1-induced UPR and α-SMA and collagen type I induction. We also showed that TGF-β1-induced UPR was mediated through the reactive oxygen species generation. Our study provides the first evidence implicating the UPR in myofibroblastic differentiation during fibrosis. These findings of the role of ER stress and chemical chaperones in pulmonary fibrosis may improve our understanding of the pathogenesis of IPF.

Endoplasmic reticulum stress in lung disease

“…Several factors linked with an increased likelihood of pulmonary fibrosis, e.g. viral infection, asbestos, amiodarone and old age, each activate the UPR in the lung, which is consistent with a potential role for ER stress in the pathogenesis of pulmonary fibrosis [10][11][12][13][14]60]. However, the link between ER stress and interstitial lung disease appears to be complex.…”

Reversal of Myofibroblast Differentiation by Prostaglandin E2

“…Previous studies have implicated FAK (30) and Akt (27) signaling, as well as endoplasmic reticulum stress (31), in myofibroblast differentiation; in addition, an epigenetic signature distinct from that of fibroblasts has been observed in myofibroblasts (32). All of these mechanisms represent potential targets that might mediate phenotypic reversal by PGE 2 ; indeed, this prostanoid is known to inhibit FAK and Akt activation (6,28), and to increase global DNA methylation in fibroblasts (33).…”

Hyperoxia and Interferon-γ–Induced Injury in Developing Lungs Occur via Cyclooxygenase-2 and the Endoplasmic Reticulum Stress–Dependent Pathway

“…Recently, a number of papers have implicated ER stressinduced cell death in adult lungs of experimental models and humans with idiopathic pulmonary fibrosis (34)(35)(36). ER stressinduced cell death has also been reported in adult lungs, secondary to oxidative stress attributable to cigarette-smoke exposure and/or chronic obstructive pulmonary disease (37)(38)(39)(40).…”