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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs
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Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs

机译：内质网应激增强肺纤维化重塑

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摘要

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 f ibrosis 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.
机译：家族性和偶发性特发性肺纤维化患者的肺部已发现内质网（ER）应激的证据。我们通过（i）在家族性间质性肺炎中发现的表面活性剂蛋白C（L188Q SFTPC）突变形式的条件表达和（ii）用蛋白错误折叠剂衣霉素进行气管内治疗来测试ER应激是引起还是加剧了肺纤维化。我们使用Tet-On系统开发了仅在II型肺泡上皮中表达L188Q SFTPC的转基因小鼠。 L188Q SFTPC的表达诱导了ER应激，这由重链Ig结合蛋白（BiP）的表达增加和X-box结合蛋白1（XBP1）mRNA的剪接确定，但在没有第二次纤维化的情况下未发现肺纤维化刺激。气管内博来霉素治疗后，与对照组相比，表达L188Q SFTPC的小鼠出现了肺纤维化过度和静态肺顺应性降低。博来霉素治疗的L188Q SFTPC小鼠还表现出肺泡上皮细胞凋亡增加和肺中成纤维细胞数量增加。对于补充模型，气管内衣霉素治疗未能诱导肺重构，但导致博来霉素诱导的纤维化增加。这些数据支持内质网应激产生功能异常的上皮细胞表型的概念，该表型促进纤维化重塑。内质网应激通路可能是特发性肺纤维化的重要治疗靶点。

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    William E. Lawson; Dong-Sheng Cheng; Amber L. Degryse; Harikrishna Tanjore; Vasiliy V. Polosukhin; Xiaochuan C. Xu; Dawn C. Newcomb; Brittany R. Jones; Juan Roldan; Kirk B. Lane; Edward E. Morrisey; Michael F. Beers; Fiona E. Yull; Timothy S. Blackwell;

  • 作者单位

    Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232,Department of Veterans Affairs Medical Center, Nashville, TN 37212;

    Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232,Fundacio Institut d'lnvestigacio Germans Trias i Pujol, Hospital Santa Caterina, Calle Dr. Castany, 17190 Salt, Spain,Servei de Pneumologia, Hospital Santa Caterina, Calle Dr. Castany, 17190 Salt, Spain;

    Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104,Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104,Penn Institute for Regenerative Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;

    Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;

    Departments of Cell Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232;

    Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232,Department of Veterans Affairs Medical Center, Nashville, TN 37212,Departments of Cell Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232,Departments of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    S100A4; unfolded protein response;

    机译：S100A4;展开的蛋白质反应;

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