title: Attenuation of warm ischemia-reperfusion injury in the liver by bucillamine through decreased neutrophil activation and Bax/Bcl-2 modulation.
abstract: OBJECTIVE
  Liver transplantation and resection surgery involve a period of ischemia and reperfusion to the liver, which initiates an inflammatory cascade resulting in liver and remote organ injury. Bucillamine is a low molecular weight thiol antioxidant that is capable of rapidly entering cells. We hypothesized that bucillamine acts by replenishing glutathione levels, thus reducing neutrophil activation, modulating Bax/Bcl-2 expression, and subsequently, attenuating the effects of warm ischemia-reperfusion injury (IRI) in the liver.
  
  
  METHODS
  The effect of bucillamine was studied in a rat model of liver IRI with 45 min of partial (70%) liver ischemia and 3 h of reperfusion. Liver injury was assessed by measuring serum transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and liver histology. Oxidative stress was quantified by measuring F(2) isoprostane and glutathione levels. Leukocyte adhesion was assessed by intravital microscopy, and inflammatory cytokine response was assessed by measuring serum cytokine-induced neutrophil chemoattractant-1 (CINC-1) levels. Bax and Bcl-2 expression was measured by reverse transcription-polymerase chain reaction.
  
  
  RESULTS
  The model produced significant liver injury with elevated transaminases and an acute inflammatory response. Bucillamine reduced the liver injury, as indicated by reduced AST (932 ± 200.8 vs 2072.5 ± 511.79, P < 0.05). Bucillamine reduced Bax expression, serum CINC-1 levels, and neutrophil adhesion, and upregulated Bcl-2. However, bucillamine did not affect tissue glutathione levels nor the levels of oxidative stress, as measured by plasma and hepatic F(2) isoprostane levels.
  
  
  CONCLUSIONS
  Bucillamine reduces warm ischemia-reperfusion in the liver by inhibiting neutrophil activation and modulating Bax/Bcl-2 expression.
authors.affiliation: Department of Surgery, Royal Free Hospital and University College London, London, UK. sameer@junnarkar.freeserve.co.uk
authors.forename: Sameer P
authors.initials: SP
authors.lastname: Junnarkar
authors.forename: Niteen
authors.initials: N
authors.lastname: Tapuria
authors.forename: Alireza
authors.initials: A
authors.lastname: Mani
authors.forename: Sas
authors.initials: S
authors.lastname: Dijk
authors.forename: Barry
authors.initials: B
authors.lastname: Fuller
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Seifalian
authors.forename: Brian R
authors.initials: BR
authors.lastname: Davidson
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D002448:Cell Adhesion / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000097:blood; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D028441:F2-Isoprostanes / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D018375:Neutrophil Activation / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D052096:Warm Ischemia / Q000009:adverse effects*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; C494828:Bax protein, rat; D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D028441:F2-Isoprostanes; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D003545:Cysteine; C026535:bucillamine