Inhibition of epithelial cell YAP-TEAD/LOX signaling attenuates pulmonary fibrosis "

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease characterized by excessive extracellular matrix (ECM) deposition. Current IPF therapies slow disease progression but do not stop or reverse it. The (myo)fibroblasts are thought to be the main cellular contributors to excessive ECM production in IPF. Here we report that fibrotic AT2 cells regulate production and crosslinking of ECM via the co-transcriptional activator YAP. YAP leads to increase expression of Lysyloxidase (LOX) and subsequent LOX mediated crosslinking by fibrotic AT2 cells. Pharmacological YAP inhibition reverses fibrotic AT2 cell reprogramming and LOX expression in experimental lung fibrosis in vivo and in human fibrotic tissue ex vivo. We thus identify YAP-TEAD/LOX inhibition in AT2 cells as a promising potential new therapy for IPF patients. In特发性肺纤维化（Idiopathic Pulmonary Fibrosis, IPF）是一种进行性且致死性的肺部疾病，其病理特征为过量细胞外基质（Extracellular Matrix, ECM）沉积。现有的IPF治疗方案仅能延缓疾病进展，无法阻断或逆转病情进展。（肌）成纤维细胞被认为是IPF患者体内过量ECM产生的主要细胞来源。本研究证实，纤维化状态的II型肺泡上皮细胞（AT2 cells）可通过共转录激活因子YAP调控ECM的合成与交联过程：YAP可上调赖氨酰氧化酶（Lysyloxidase, LOX）的表达，并经由LOX介导纤维化AT2细胞的ECM交联反应。在体内实验性肺纤维化模型与离体人纤维化肺组织中，通过药理学手段抑制YAP，可逆转纤维化AT2细胞的重编程过程并下调LOX的表达水平。据此，本研究确认在AT2细胞中靶向抑制YAP-TEAD/LOX通路，有望成为IPF患者的潜在新型治疗方案。