Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine.
Department of Materials Science and Engineering, and.
JCI Insight. 2019 Apr 4;4(7). doi: 10.1172/jci.insight.123253.
Idiopathic pulmonary fibrosis (IPF) is a progressive disease, with a median survival of 3-5 years following diagnosis. Lung remodeling by invasive fibroblasts is a hallmark of IPF. In this study, we demonstrate that inhibition of vimentin intermediate filaments (VimIFs) decreases the invasiveness of IPF fibroblasts and confers protection against fibrosis in a murine model of experimental lung injury. Increased expression and organization of VimIFs contribute to the invasive property of IPF fibroblasts in connection with deficient cellular autophagy. Blocking VimIF assembly by pharmacologic and genetic means also increases autophagic clearance of collagen type I. Furthermore, inhibition of expression of collagen type I by siRNA decreased invasiveness of fibroblasts. In a bleomycin injury model, enhancing autophagy in fibroblasts by an inhibitor of VimIF assembly, withaferin A (WFA), protected from fibrotic lung injury. Additionally, in 3D lung organoids, or pulmospheres, from patients with IPF, WFA reduced the invasiveness of lung fibroblasts in the majority of subjects tested. These studies provide insights into the functional role of vimentin, which regulates autophagy and restricts the invasiveness of lung fibroblasts.
特发性肺纤维化（IPF）是一种进行性疾病，确诊后中位生存期为 3-5 年。肺成纤维细胞的侵袭性重塑是 IPF 的标志。在这项研究中，我们证明抑制中间丝波形蛋白（VimIFs）可降低 IPF 成纤维细胞的侵袭性，并在实验性肺损伤的小鼠模型中提供抗纤维化保护。VimIFs 的表达和组织增加有助于与细胞自噬缺陷相关的 IPF 成纤维细胞的侵袭特性。通过药理学和遗传学方法阻断 VimIF 组装也会增加 I 型胶原的自噬清除。此外，通过 siRNA 抑制 I 型胶原的表达降低了成纤维细胞的侵袭性。在博来霉素损伤模型中，通过抑制 VimIF 组装的抑制剂（吴茱萸碱，WFA）增强成纤维细胞中的自噬，可防止纤维性肺损伤。此外，在来自 IPF 患者的 3D 肺类器官或肺球体中，WFA 降低了大多数测试对象的肺成纤维细胞的侵袭性。这些研究深入了解了波形蛋白的功能作用，它调节自噬并限制肺成纤维细胞的侵袭性。
