1. Academic Validation
  2. Nintedanib Inhibits Endothelial Mesenchymal Transition in Bleomycin-Induced Pulmonary Fibrosis via Focal Adhesion Kinase Activity Reduction

Nintedanib Inhibits Endothelial Mesenchymal Transition in Bleomycin-Induced Pulmonary Fibrosis via Focal Adhesion Kinase Activity Reduction

  • Int J Mol Sci. 2022 Jul 25;23(15):8193. doi: 10.3390/ijms23158193.
Wen-Kuang Yu 1 2 Wei-Chih Chen 1 2 3 Vincent Yi-Fong Su 2 4 Hsiao-Chin Shen 1 Huai-Hsuan Wu 1 Hao Chen 1 Kuang-Yao Yang 1 2 3 5
Affiliations

Affiliations

  • 1 Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
  • 2 School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan.
  • 3 Institute of Emergency and Critical Care Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan.
  • 4 Department of Internal Medicine, Taipei City Hospital, Taipei 11217, Taiwan.
  • 5 Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan.
Abstract

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.

Keywords

bleomycin-induced pulmonary fibrosis; endothelial mesenchymal transition; focal adhesion kinase; idiopathic pulmonary fibrosis; nintedanib.

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