Journal Article

Nintedanib reduces ventilation‐augmented bleomycin‐induced epithelial–mesenchymal transition and lung fibrosis through suppression of the Src pathway

Li, Li‐Fu, Liu, Yung‐Yang, Kao, Kuo‐Chin, Chen, Ning‐Hung, Lee, Chung‐Shu, Yang, Cheng‐Ta, Lin, Chang‐Wei, Wang, Chih‐Wei

2017

Overview

Mechanical ventilation (MV) used in patients with acute respiratory distress syndrome (ARDS) can increase lung inflammation and pulmonary fibrogenesis. Src is crucial in mediating the transforming growth factor (TGF)‐β1‐induced epithelial–mesenchymal transition (EMT) during the fibroproliferative phase of ARDS. Nintedanib, a multitargeted tyrosine kinase inhibitor that directly blocks Src, has been approved for the treatment of idiopathic pulmonary fibrosis. The mechanisms regulating interactions among MV, EMT and Src remain unclear. In this study, we suggested hypothesized that nintedanib can suppress MV‐augmented bleomycin‐induced EMT and pulmonary fibrosis by inhibiting the Src pathway. Five days after administrating bleomycin to mimic acute lung injury (ALI), C57BL/6 mice, either wild‐type or Src‐deficient were exposed to low tidal volume (VT) (6 ml/kg) or high VT (30 ml/kg) MV with room air for 5 hrs. Oral nintedanib was administered once daily in doses of 30, 60 and 100 mg/kg for 5 days before MV. Non‐ventilated mice were used as control groups. Following bleomycin exposure in wild‐type mice, high VT MV induced substantial increases in microvascular permeability, TGF‐β1, malondialdehyde, Masson's trichrome staining, collagen 1a1 gene expression, EMT (identified by colocalization of increased staining of α‐smooth muscle actin and decreased staining of E‐cadherin) and alveolar epithelial apoptosis (P < 0.05). Oral nintedanib, which simulated genetic downregulation of Src signalling using Src‐deficient mice, dampened the MV‐augmented profibrotic mediators, EMT profile, epithelial apoptotic cell death and pathologic fibrotic scores (P < 0.05). Our data indicate that nintedanib reduces high VT MV‐augmented EMT and pulmonary fibrosis after bleomycin‐induced ALI, partly by inhibiting the Src pathway.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Actin / Actins - genetics / Actins - metabolism / Acute Lung Injury - chemically induced / Acute Lung Injury - drug therapy / Acute Lung Injury - genetics / Acute Lung Injury - metabolism / Administration, Oral / Alveoli / Animals / Anti-Inflammatory Agents - pharmacology / Apoptosis / Bleomycin / Bleomycin - toxicity / Cadherins - genetics / Cadherins - metabolism / Cell death / Collagen / Collagen Type I - genetics / Collagen Type I - metabolism / Disease Models, Animal / Drug Administration Schedule / E-cadherin / Enzyme inhibitors / Epithelial-Mesenchymal Transition - drug effects / Epithelial-Mesenchymal Transition - genetics / epithelial–mesenchymal transition / Fibrosis / Gene expression / Gene Expression Regulation / Humans / Indoles - pharmacology / Kinases / Lung - drug effects / Lung - metabolism / Lung - pathology / Lung diseases / Malondialdehyde / Mechanical ventilation / Mesenchyme / Mice / Mice, Inbred C57BL / Mice, Knockout / Microvasculature / nintedanib / Original / Permeability / Protein-tyrosine kinase / Pulmonary fibrosis / Pulmonary Fibrosis - chemically induced / Pulmonary Fibrosis - drug therapy / Pulmonary Fibrosis - genetics / Pulmonary Fibrosis - metabolism / Respiration, Artificial - adverse effects / Respiratory distress syndrome / Rodents / Signal Transduction / Smooth muscle / Src / src-Family Kinases - antagonists & inhibitors / src-Family Kinases - deficiency / src-Family Kinases - genetics / Tidal Volume / Transforming Growth Factor beta1 - genetics / Transforming Growth Factor beta1 - metabolism / Transforming growth factor-b1 / Ventilation / Ventilator-Induced Lung Injury - drug therapy / Ventilator-Induced Lung Injury - etiology / Ventilator-Induced Lung Injury - genetics / Ventilator-Induced Lung Injury - metabolism / ventilator‐induced lung injury