title: Caspase-3 inhibition prevents the development of hepatopulmonary syndrome in common bile duct ligation rats by alleviating pulmonary injury.
abstract: OBJECTIVE
  Common bile duct ligation (CBDL) rats is an accepted experimental model of hepatopulmonary syndrome (HPS), defined as liver disease and intrapulmonary vascular dilatation and hypoxaemia. Pulmonary Akt and ERK activation followed by angiogenesis in the later stages of CBDL, contribute to the pathogenesis of HPS. However, the mechanisms behind Akt and ERK activation remain undefined. Pulmonary injury induced by increased bilirubin, endotoxin and inflammatory mediators occurs in the early stages of CBDL. We assessed the effects of relieving pulmonary injury on Akt and ERK activation and on the development of HPS following CBDL.
  
  
  METHODS
  Pulmonary injury, angiogenesis, arterial oxygenation, cell proliferation and, phospho-Akt and ERK1 were evaluated in CBDL animals with or without caspase-3 inhibition (Z-DEVD-FMK). Pulmonary injury was assessed by histology and quantifying apoptosis and aquaporin-1 (AQP1) levels. Lung angiogenesis was assessed by quantifying AQP1 level, vWF-positive cells and microvessel count.
  
  
  RESULTS
  Pulmonary apoptosis and caspase-3 activation were markedly increased in the early stages of CBDL. Caspase-3 inhibition alleviated apoptosis, the reduction in AQP1, phospho-Akt and ERK1 levels and pulmonary injury 1 week after CBDL. Caspase-3 inhibition also reduced AQP1, phospho-Akt and ERK1 levels, vWF-positive cells, cell proliferation, microvessel count, and microvascular dilatation and improved arterial oxygenation 3 weeks following CBDL.
  
  
  CONCLUSIONS
  Caspase-3 inhibition alleviates pulmonary injury, thereby preventing angiogenesis as well as the development of HPS in CBDL rats. These effects are related to the regulation of the Akt and ERK1 pathways.
authors.affiliation: Department of Anesthesia, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
authors.forename: Jiao L
authors.initials: JL
authors.lastname: Ning
authors.forename: Jian T
authors.initials: JT
authors.lastname: Gu
authors.forename: Jian
authors.initials: J
authors.lastname: Cui
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Zeng
authors.forename: Bin
authors.initials: B
authors.lastname: Yi
authors.forename: Kai Z
authors.initials: KZ
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051398:Aquaporin 1 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003135:Common Bile Duct / Q000601:surgery*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D020065:Hepatopulmonary Syndrome / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008026:Ligation; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D055370:Lung Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D010100:Oxygen / Q000097:blood; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: C496022:Aqp1 protein, rat; D061945:Caspase Inhibitors; D009842:Oligopeptides; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D014841:von Willebrand Factor; D051398:Aquaporin 1; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3; C505410:Casp3 protein, rat; D053148:Caspase 3; D010100:Oxygen
keywords: angiogenesis; apoptosis; common bile duct ligation; hepatopulmonary syndrome; injury