title: Mechanical ventilation augments bleomycin-induced epithelial-mesenchymal transition through the Src pathway.
abstract: Mechanical ventilation used in patients with acute respiratory distress syndrome (ARDS) can damage pulmonary epithelial cells by producing inflammatory cytokines and depositing excess collagen. Src participates in plasminogen activator inhibitor-1 (PAI-1) and transforming growth factor-β1(TGF-β1) production during the fibroproliferative phase of ARDS, which involves a process of epithelial-mesenchymal transition (EMT). The mechanisms regulating interactions between mechanical ventilation and EMT are unclear. We hypothesized that EMT induced by high-tidal volume (VT) mechanical stretch-augmented lung inflammation occurs through upregulation of the Src pathway. Five days after administering bleomycin to simulate acute lung injury (ALI), male C57BL/6 mice, either wild-type or Src-deficient, aged 3 months, weighing between 25 and 30 g, were exposed to low-VT (6 ml/kg) or high-VT (30 ml/kg) mechanical ventilation with room air for 1-5 h. Nonventilated mice were used as control subjects. We observed that high-VT mechanical ventilation increased microvascular permeability, PAI-1 and TGF-β1 protein levels, Masson's trichrome staining, extracellular collagen levels, collagen gene expression, fibroblast accumulation, positive staining of α-smooth muscle actin and type I collagen, activation of Src signaling and epithelial apoptotic cell death in wild-type mice (P<0.05). Decreased staining of the epithelial marker, Zonula occludents-1, was also observed. Mechanical stretch-augmented EMT and epithelial apoptosis were attenuated in Src-deficient mice and pharmacological inhibition of Src activity by PP2 (P<0.05). Our data suggest that high-VT mechanical ventilation-augmented EMT after bleomycin-induced ALI partially depends on the Src pathway.
authors: 1] Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan [2] Department of Respiratory Therapy, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors: Li-Fu
authors: LF
authors: Li
authors: 1] Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan [2] Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors: Yung-Yang
authors: YY
authors: Liu
authors: 1] Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan [2] Department of Respiratory Therapy, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors: Kuo-Chin
authors: KC
authors: Kao
authors: 1] Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Taoyuan, Taiwan [2] Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.
authors: Chen-Te
authors: CT
authors: Wu
authors: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors: Chih-Hao
authors: CH
authors: Chang
authors: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors: Chen-Yiu
authors: CY
authors: Hung
authors: 1] Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan [2] Department of Respiratory Therapy, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors: Cheng-Ta
authors: CT
authors: Yang
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012121:Respiration, Artificial
chemical_list: D001761:Bleomycin; D016392:Proto-Oncogene Proteins pp60(c-src)