Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan.
Int J Mol Sci. 2022 Jul 25;23(15):8193. doi: 10.3390/ijms23158193.
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD). Pulmonary fibroblasts play an important role in the development of IPF. Emerging evidence indicates that pulmonary endothelial cells could be the source of pulmonary fibroblasts through endothelial mesenchymal transition (EndoMT), which contributes to pulmonary fibrosis. EndoMT is a complex process in which endothelial cells lose their expression of endothelial markers and give rise to the characteristics of mesenchymal cells, including morphological fibroblast-like change and the expression of mesenchymal markers, which result in cardiac, renal, and dermal fibroses. Furthermore, EndoMT inhibition attenuates pulmonary fibrosis. Herein, we demonstrate that nintedanib, a tyrosine kinase receptor inhibitor, ameliorated murine bleomycin (BLM)-induced pulmonary fibrosis and suppressed the in vivo and in vitro models of EndoMT. We demonstrated that the activity of focal adhesion kinase (FAK), a key EndoMT regulator, increased in murine lung tissues and human pulmonary microvascular endothelial cells after BLM stimulation. Nintedanib treatment inhibited BLM-induced FAK activation and thus suppressed both in vivo and in vitro BLM-induced EndoMT. Importantly, we found that the VEGF/FAK signaling pathway was involved in nintedanib regulating EndoMT. These novel findings help us understand the mechanism and signaling pathway of EndoMT to further develop more efficacious drugs for IPF treatment.
特发性肺纤维化（IPF）是一种进行性间质性肺疾病（ILD）。肺成纤维细胞在 IPF 的发展中起着重要作用。新出现的证据表明，肺内皮细胞可能通过内皮间充质转化（EndoMT）成为肺成纤维细胞的来源，这有助于肺纤维化。EndoMT 是一个复杂的过程，在此过程中内皮细胞丧失内皮标志物的表达，并产生间充质细胞的特征，包括形态上的成纤维细胞样变化和间充质标志物的表达，导致心脏、肾脏和皮肤纤维化。此外，EndoMT 抑制可减轻肺纤维化。在此，我们证明了一种酪氨酸激酶受体抑制剂尼达尼布可改善博来霉素（BLM）诱导的小鼠肺纤维化，并抑制体内和体外的 EndoMT 模型。我们证明了 BLM 刺激后，在小鼠肺组织和人肺微血管内皮细胞中，焦点黏附激酶（FAK）的活性，一种关键的 EndoMT 调节剂增加。尼达尼布治疗抑制 BLM 诱导的 FAK 激活，从而抑制体内和体外 BLM 诱导的 EndoMT。重要的是，我们发现 VEGF/FAK 信号通路参与了尼达尼布调节 EndoMT。这些新发现有助于我们了解 EndoMT 的机制和信号通路，从而进一步开发更有效的 IPF 治疗药物。
