Inhibition of focal adhesion kinase prevents experimental lung fibrosis and myofibroblast formation.
Inhibition of focal adhesion kinase prevents experimental lung fibrosis and myofibroblast formation.
复制标题
DOI：
10.1002/art.33482
复制
发表时间：
2012-05
影响因子：
--
通讯作者：
Rodriguez-Pascual, Fernando
中科院分区：
文献类型：
--
作者：
Lagares, David;Busnadiego, Oscar;Garcia-Fernandez, Rosa Ana;Kapoor, Mohit;Liu, Shangxi;Carter, David E.;Abraham, David;Shi-Wen, Xu;Carreira, Patricia;Fontaine, Benjamin A.;Shea, Barry S.;Tager, Andrew M.;Leask, Andrew;Lamas, Santiago;Rodriguez-Pascual, Fernando
增强的粘附信号传导，包括粘着斑激酶 (FAK) 的激活，是肺纤维化患者成纤维细胞的标志，因此，FAK 被假设为这种疾病的关键介质。本研究旨在表征 FAK 对体内和体外肺纤维化发展的贡献。通过免疫组织化学分析肺纤维化患者肺组织样本中的 FAK 表达和活性。口服 FAK 抑制剂 PF-562,271 或 siRNA 介导的 FAK 沉默处理的小鼠，暴露于气管内滴注博来霉素以诱导肺纤维化，并收获肺用于组织学和生化分析。使用内皮素-1 (ET-1) 作为刺激物，在从野生型和 FAK 缺陷型小鼠胚胎中分离的成纤维细胞中研究细胞粘附和收缩以及促纤维化基因表达。在原代小鼠肺成纤维细胞以及野生型和整合素 β1 缺陷型成纤维细胞中研究了 ET-1 介导的 FAK 激活和基因表达。肺纤维化患者的成纤维细胞灶和血管重塑中 FAK 表达和活性增加。药理学或 siRNA 介导的 FAK 靶向可显着消除博莱霉素诱导的肺纤维化。 FAK 的缺失会损害对 ET-1 响应的促纤维化表型的获得。导致肌成纤维细胞分化的促纤维化基因表达需要细胞粘附，并由 Jun N 末端激酶通过整联蛋白 β1/FAK 信号传导激活驱动。这些结果表明 FAK 是纤维发生的中心介质，并强调该激酶作为纤维化疾病的潜在治疗靶点。
Enhanced adhesive signaling including activation of the focal adhesion kinase (FAK) is a hallmark of fibroblasts from lung fibrosis patients, and FAK has been therefore hypothesized to be a key mediator of this disease. This study was undertaken to characterize the contribution of FAK to the development of pulmonary fibrosis both in vivo and in vitro. FAK expression and activity were analyzed in lung tissue samples from lung fibrosis patients by immunohistochemistry. Mice orally treated with the FAK inhibitor, PF-562,271, or with siRNA-mediated silencing of FAK, were exposed to intratracheally instilled bleomycin to induce lung fibrosis, and the lungs were harvested for histological and biochemical analysis. Using endothelin-1 (ET-1) as stimulus, cell adhesion and contraction, as well as profibrotic gene expression were studied in fibroblasts isolated from wild type and FAK-deficient mouse embryos. ET-1-mediated FAK activation and gene expression were studied in primary mouse lung fibroblasts, as well as in wild type and integrin β1-deficient fibroblasts. Increased FAK expression and activity are upregulated in fibroblast foci and remodeled vessels in lung fibrosis patients. Pharmacological or siRNA-mediated targeting of FAK resulted in marked abrogation of bleomycin-induced lung fibrosis. Loss of FAK impaired the acquisition of a profibrotic phenotype in response to ET-1. Profibrotic gene expression leading to myofibroblast differentiation required cell adhesion, and was driven by Jun N-terminal kinase activation through integrin β1/FAK signaling. These results implicate FAK as a central mediator of fibrogenesis, and highlight this kinase as a potential therapeutic target in fibrotic diseases.
登录
查看更多内容
影响因子：
4.8
作者：
Daher, Zeinab;Noel, Josette;Claing, Audrey
通讯作者：
Claing, Audrey
DOI：
10.7326/0003-4819-142-12_part_1-200506210-00005
发表时间：
2005-06-21
影响因子：
39.2
作者：
Martinez, FJ;Safrin, S;Brown, KK
通讯作者：
Brown, KK
影响因子：
3.3
作者：
Liu, Shangxi;Xu Shi-wen;Leask, Andrew
通讯作者：
Leask, Andrew
影响因子：
6.2
作者：
Bagi, Cedo M.;Roberts, Gregory W.;Andresen, Catharine J.
通讯作者：
Andresen, Catharine J.
影响因子：
5
作者：
FASSKE, E;MORGENROTH, K
通讯作者：
MORGENROTH, K