Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA.
Department of Chemical Engineering, Stanford University, Stanford, California, USA.
Adv Wound Care (New Rochelle). 2022 Oct;11(10):511-523. doi: 10.1089/wound.2021.0077. Epub 2021 Nov 30.
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that affects 63 in every 100,000 Americans. Its etiology remains unknown, although inflammatory pathways appear to be important. Given the dynamic environment of the lung, we examined the significance of mechanotransduction on both inflammatory and fibrotic signaling during IPF. Mechanotransduction pathways have not been thoroughly examined in the context of lung disease, and pharmacologic approaches for IPF do not currently target these pathways. The interplay between mechanical strain and inflammation in pulmonary fibrosis remains incompletely understood. In this study, we used conditional KO mice to block mechanotransduction by knocking out Focal Adhesion Kinase (FAK) expression in fibroblasts, followed by induction of pulmonary fibrosis using bleomycin. We examined both normal human and human IPF fibroblasts and used immunohistochemistry, quantitative real-time polymerase chain reaction, and Western Blot to evaluate the effects of FAK inhibitor (FAK-I) on modulating fibrotic and inflammatory genes. Our data indicate that the deletion of FAK in mice reduces expression of fibrotic and inflammatory genes in lungs. Similarly, mechanical straining in normal human lung fibroblasts activates inflammatory and fibrotic pathways. The FAK inhibition decreases these signals but has a less effect on IPF fibroblasts as compared with normal human fibroblasts. Administering FAK-I at early stages of fibrosis may attenuate the FAK-mediated fibrotic response pathway in IPF, potentially mediating disease progression.
特发性肺纤维化（IPF）是一种进行性肺纤维化疾病，影响每 10 万人中有 63 人。其病因仍不清楚，尽管炎症途径似乎很重要。鉴于肺部的动态环境，我们研究了机械转导在 IPF 中的炎症和纤维化信号中的意义。在肺部疾病的背景下，尚未对机械转导途径进行彻底检查，目前针对 IPF 的药物治疗方法也未针对这些途径。机械应变与肺纤维化中的炎症之间的相互作用仍不完全清楚。在这项研究中，我们使用条件性 KO 小鼠敲除成纤维细胞中的粘着斑激酶（FAK）表达，从而阻断机械转导，然后使用博来霉素诱导肺纤维化。我们研究了正常人和 IPF 人的成纤维细胞，并使用免疫组织化学、实时定量聚合酶链反应和 Western Blot 来评估 FAK 抑制剂（FAK-I）对调节纤维化和炎症基因的影响。我们的数据表明，在小鼠中敲除 FAK 可减少肺部纤维化和炎症基因的表达。同样，正常人类肺成纤维细胞的机械应变激活了炎症和纤维化途径。FAK 抑制可降低这些信号，但与正常人类成纤维细胞相比，对 IPF 成纤维细胞的作用较小。在纤维化的早期阶段给予 FAK-I 可能会减弱 IPF 中的 FAK 介导的纤维化反应途径，从而潜在地介导疾病进展。
