title: 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.
authors.affiliation: Department of Pathology, Chonbuk National University Medical School, San 2-20 Keumam-Dong, Dukjin-gu, Jeonju, Korea.
authors.forename: Hyun Ah
authors.initials: HA
authors.lastname: Baek
authors.forename: Do Sung
authors.initials: DS
authors.lastname: Kim
authors.forename: Ho Sung
authors.initials: HS
authors.lastname: Park
authors.forename: Kyu Yun
authors.initials: KY
authors.lastname: Jang
authors.forename: Myoung Jae
authors.initials: MJ
authors.lastname: Kang
authors.forename: Dong Geun
authors.initials: DG
authors.lastname: Lee
authors.forename: Woo Sung
authors.initials: WS
authors.lastname: Moon
authors.forename: Han Jung
authors.initials: HJ
authors.lastname: Chae
authors.forename: Myoung Ja
authors.initials: MJ
authors.lastname: Chung
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005347:Fibroblasts / Q000166:cytology*; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress