Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs
Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs
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DOI：
10.1073/pnas.1107559108
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发表时间：
2011-06-28
影响因子：
11.1
通讯作者：
Blackwell, Timothy S.
中科院分区：
文献类型：
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作者：
Lawson, William E.;Cheng, Dong-Sheng;Blackwell, Timothy S.
在家族性和散发性特发性肺纤维化患者的肺中发现了内质网（ER）应激的证据。我们通过（i）家族性间质性肺炎中发现的表面活性蛋白C（L188 Q SFTPC）突变形式的条件表达和（ii）蛋白质错误折叠剂衣霉素的肠内治疗来测试ER应激是否引起或加重肺纤维化。我们开发的转基因小鼠表达L188 Q SFTPC只在II型肺泡上皮细胞通过使用Tet-On系统。L188 Q SFTPC的表达诱导ER应激，如通过增加重链IG结合蛋白（BiP）的表达和X-box结合蛋白1（XBP 1）mRNA的剪接所确定的，但是在没有第二促纤维化刺激的情况下没有鉴定出肺纤维化。经气管内博莱霉素治疗后，与对照组相比，表达L188 Q SFTPC的小鼠发生了加重的肺纤维化和降低的静态肺顺应性。博来霉素处理的L188 Q SFTPC小鼠也表现出肺泡上皮细胞的凋亡增加和肺中成纤维细胞的数量增加。在一个补充模型中，经皮腔内衣霉素治疗未能诱导肺重塑，但导致博莱霉素诱导的纤维化增加。这些数据支持ER应激产生功能障碍的上皮细胞表型，促进纤维化重塑的概念。ER应激通路可能成为特发性肺纤维化的重要治疗靶点。
Evidence of endoplasmic reticulum (ER) stress has been found in lungs of patients with familial and sporadic idiopathic pulmonary fibrosis. We tested whether ER stress causes or exacerbates lung fibrosis by (i) conditional expression of a mutant form of surfactant protein C (L188Q SFTPC) found in familial interstitial pneumonia and (ii) intratracheal treatment with the protein misfolding agent tunicamycin. We developed transgenic mice expressing L188Q SFTPC exclusively in type II alveolar epithelium by using the Tet-On system. Expression of L188Q SFTPC induced ER stress, as determined by increased expression of heavy-chain Ig binding protein (BiP) and splicing of X-box binding protein 1 (XBP1) mRNA, but no lung fibrosis was identified in the absence of a second profibrotic stimulus. After intratracheal bleomycin, L188Q SFTPC-expressing mice developed exaggerated lung fibrosis and reduced static lung compliance compared with controls. Bleomycin-treated L188Q SFTPC mice also demonstrated increased apoptosis of alveolar epithelial cells and greater numbers of fibroblasts in the lungs. With a complementary model, intratracheal tunicamycin treatment failed to induce lung remodeling yet resulted in augmentation of bleomycin-induced fibrosis. These data support the concept that ER stress produces a dysfunctional epithelial cell phenotype that facilitates fibrotic remodeling. ER stress pathways may serve as important therapeutic targets in idiopathic pulmonary fibrosis.