title: Activation of Src-dependent Smad3 signaling mediates the neutrophilic inflammation and oxidative stress in hyperoxia-augmented ventilator-induced lung injury.
abstract: BACKGROUND
  Mechanical ventilation and concomitant administration of hyperoxia in patients with acute respiratory distress syndrome can damage the alveolar epithelial and capillary endothelial barrier by producing inflammatory cytokines and reactive oxygen species. The Src tyrosine kinase and Smad3 are crucial inflammatory regulators used for ventilator-induced lung injury (VILI). The mechanisms regulating interactions between high-tidal-volume mechanical ventilation, hyperoxia, and acute lung injury (ALI) are unclear. We hypothesized that high-tidal-volume mechanical stretches and hyperoxia augment lung inflammation through upregulation of the Src and Smad3 pathways.
  
  
  METHODS
  Wild-type or Src-deficient C57BL/6 mice, aged between 6 and 8 weeks, were exposed to high-tidal-volume (30 mL/kg) ventilation with room air or hyperoxia for 1-4 h after 2-mg/kg Smad3 inhibitor (SIS3) administration. Nonventilated mice were used as control subjects.
  
  
  RESULTS
  We observed that the addition of hyperoxia to high-tidal-volume mechanical ventilation further induced microvascular permeability, neutrophil infiltration, macrophage inflammatory protein-2 and matrix metalloproteinase-9 (MMP-9) production, malondialdehyde, nicotinamide adenine dinucleotide phosphate oxidase activity, MMP-9 mRNA expression, hypoxemia, and Src and Smad3 activation (P < 0.05). Hyperoxia-induced augmentation of VILI was attenuated in Src-deficient mice and mice with pharmacological inhibition of Smad3 activity by SIS3 (P < 0.05). Mechanical ventilation of Src-deficient mice with hyperoxia further reduced the activation of Smad3.
  
  
  CONCLUSIONS
  Our data suggest that hyperoxia-increased high-tidal-volume ventilation-induced ALI partially depends on the Src and Smad3 pathways.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, 5 Fu-Hsing Street, Kweishan, Taoyuan, 333, Taiwan.|Department of Respiratory Therapy, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Li-Fu
authors.initials: LF
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, 5 Fu-Hsing Street, Kweishan, Taoyuan, 333, Taiwan.
authors.forename: Chung-Shu
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yung-Yang
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, 5 Fu-Hsing Street, Kweishan, Taoyuan, 333, Taiwan.
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, 5 Fu-Hsing Street, Kweishan, Taoyuan, 333, Taiwan.
authors.forename: Chang-Wei
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, 5 Fu-Hsing Street, Kweishan, Taoyuan, 333, Taiwan.
authors.forename: Li-Chung
authors.initials: LC
authors.lastname: Chiu
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, 5 Fu-Hsing Street, Kweishan, Taoyuan, 333, Taiwan.|Department of Respiratory Therapy, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Kuo-Chin
authors.initials: KC
authors.lastname: Kao
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, 5 Fu-Hsing Street, Kweishan, Taoyuan, 333, Taiwan.|Department of Respiratory Therapy, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Ning-Hung
authors.initials: NH
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, 5 Fu-Hsing Street, Kweishan, Taoyuan, 333, Taiwan. yang1946@cgmh.org.tw.|Department of Respiratory Therapy, Chang Gung Memorial Hospital, Taoyuan, Taiwan. yang1946@cgmh.org.tw.
authors.forename: Cheng-Ta
authors.initials: CT
authors.lastname: Yang
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D054426:Chemokine CXCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D018496:Hyperoxia / Q000150:complications*; D007546:Isoquinolines / Q000494:pharmacology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D011014:Pneumonia / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012121:Respiration, Artificial / Q000009:adverse effects*; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013990:Tidal Volume; D055397:Ventilator-Induced Lung Injury / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C508504:6,7-dimethyl-2-(2E)-3-(1-methyl-2-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl-prop-2-enoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D007546:Isoquinolines; D011725:Pyridines; D011758:Pyrroles; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D019255:NADPH Oxidases; D019061:src-Family Kinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse