Involvement of Endoplasmic Reticulum Stress in Myofibroblastic Differentiation of Lung Fibroblasts
Involvement of Endoplasmic Reticulum Stress in Myofibroblastic Differentiation of Lung Fibroblasts
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DOI：
10.1165/rcmb.2011-0121oc
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发表时间：
2012-06-01
影响因子：
6.4
通讯作者：
Chung, Myoung Ja
中科院分区：
文献类型：
--
作者：
Baek, Hyun Ah;Kim, Do Sung;Chung, Myoung Ja
损伤内质网（ER）功能的应激导致未折叠或错误折叠的蛋白质在ER中的积累（ER应激），并触发未折叠蛋白质反应（UPR）。最近的研究表明，ER应激参与特发性肺纤维化（IPF）。本研究旨在探讨内质网应激对成纤维细胞向肌纤维母细胞分化的作用。IPF成纤维细胞灶中的成纤维细胞显示GRP 78免疫反应性。为了确定ER应激对成纤维细胞中α-平滑肌肌动蛋白（α-SMA）和I型胶原蛋白表达的作用，用TGF-β 1处理小鼠和人肺成纤维细胞，并通过Western印迹分析ER应激相关蛋白、α-SMA和I型胶原蛋白的表达。TGF-β 1显著增加GRP 78、XBP-1和ATF 6 α的表达，同时伴随着小鼠和人成纤维细胞中α-SMA和I型胶原蛋白表达的增加。化学伴侣4-PBA抑制TGF-β 1诱导的UPR和α-SMA和I型胶原诱导。我们还发现，TGF-β 1诱导的UPR是通过活性氧的产生介导的。我们的研究提供了第一个证据表明UPR在纤维化过程中的肌纤维母细胞分化。ER应激和化学分子伴侣在肺纤维化中作用的这些发现可能会提高我们对IPF发病机制的理解。
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 alpha-smooth muscle actin (alpha-SMA) and collagen type I expression in fibroblasts, mouse and human lung fibroblasts were treated with TGF-beta 1, and expression of ER stress-related proteins, alpha-SMA, and collagen type I was analyzed by Western blotting. TGF-beta 1 significantly increased expression of GRP78, XBP-1, and ATF6 alpha, which was accompanied by increases in alpha-SMA and collagen type I expression in mouse and human fibroblasts. A chemical chaperone, 4-PBA, suppressed TGF-beta 1-induced UPR and alpha-SMA and collagen type I induction. We also showed that TGF-beta 1-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.