Activation of Src-dependent Smad3 signaling mediates the neutrophilic inflammation and oxidative stress in hyperoxia-augmented ventilator-induced lung injury

Respiratory Research

Cheng-Ta Yang³  Ning-Hung Chen³  Kuo-Chin Kao³  Li-Chung Chiu²  Chang-Wei Lin²  Chih-Hao Chang²  Yung-Yang Liu¹  Chung-Shu Lee²  Li-Fu Li³ 

[1] Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan;Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital and Chang Gung University, 5 Fu-Hsing Street, Taoyuan 333, Kweishan, Taiwan;Department of Respiratory Therapy, Chang Gung Memorial Hospital, Taoyuan, Taiwan

关键词: Ventilator-induced lung injury;    Src;    Smad3;    Nicotinamide adenine dinucleotide phosphate oxidase;    Matrix metalloproteinase-9;    Hyperoxia;   

Others  :  1233523
DOI  :  10.1186/s12931-015-0275-6

 received in 2015-05-18, accepted in 2015-09-10,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Li et al.

【 图 表 】

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