title: Hepatic Warm Ischemia-Reperfusion-Induced Increase in Pulmonary Capillary Filtration Is Ameliorated by Administration of a Multidrug Resistance-Associated Protein 1 Inhibitor and Leukotriene D4 Antagonist (MK-571) Through Reducing Neutrophil Infiltration and Pulmonary Inflammation and Oxidative Stress in Rats.
abstract: BACKGROUND
  Hepatopulmonary syndrome (HPS) is the major complication subsequent to liver ischemia and reperfusion (I/R) injury after resection or transplantation of liver. Hallmarks of HPS include increases in pulmonary leukotrienes and neutrophil recruitment and infiltrating across capillaries. We aimed to investigate the protective efficacy of MK-571, a multidrug resistance-associated protein 1 inhibitor and leukotriene D4 agonist, against hepatic I/R injury-associated change in capillary filtration.
  
  
  METHODS
  Eighteen Sprague-Dawley male rats were evenly divided into a sham-operated group, a hepatic I/R group, and an MK-571-treated I/R group. MK-571 was administered intraperitoneally 15 min before hepatic ischemia and every 12 hours during reperfusion. Ischemia was conducted by occluding the hepatic artery and portal vein for 30 min, followed by removing the clamps and closing the incision. Forty-eight hours after hepatic ischemia, we assessed the pulmonary capillary filtration coefficient (Kfc) through the use of in vitro-isolated, perfused rat lung preparation. We also measured the lung wet-to-dry weight ratio (W/D) and protein concentration in broncho-alveolar lavage fluid (PCBAL). Lung inflammation and oxidative stress were evaluated by use of tissue tumor necrosis factor (TNF)-α and malondialdehyde levels and lavage differential macrophage and neutrophil cell count.
  
  
  RESULTS
  Hepatic I/R injury markedly increased Kfc, W/D, PCBAL, tissue TNF-α level, and differential neutrophil cell count (P < .05). MK-571 treatment reduced neutrophil infiltration and lung inflammation and improved pulmonary capillary filtration, collectively suggesting lung protection.
  
  
  CONCLUSIONS
  Treatment with MK-571 before and during hepatic ischemia and reperfusion protects lung against pulmonary capillary barrier function impairment through decreasing pulmonary lung inflammation and lavage neutrophils.
authors.affiliation: Division of Chest Medicine, Internal Medicine, Shin Kong Wu-Ho-Su Memorial Hospital, Taipei, Taiwan; School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
authors.forename: D Y-W
authors.initials: DY
authors.lastname: Yeh
authors.affiliation: School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Yang
authors.affiliation: School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan. Electronic address: 078625@mail.fju.edu.tw.
authors.forename: J-J
authors.initials: JJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020024:Leukotriene Antagonists / Q000008:administration & dosage; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000008:administration & dosage*; D020556:Neutrophil Infiltration / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D011422:Propionates / Q000008:administration & dosage*; D011804:Quinolines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D052096:Warm Ischemia / Q000379:methods*
chemical_list: D020024:Leukotriene Antagonists; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; C059141:verlukast; C421109:multidrug resistance-associated protein 1