title: Bromelain ameliorates hepatic microcirculation after warm ischemia.
abstract: BACKGROUND
  Because of its immunomodulatory action, the protease bromelain represents a novel strategy for the treatment of hepatic ischemia/reperfusion (I/R) injury. A dose-response study was performed to investigate the effect of bromelain on liver function, microcirculation, and leukocyte-endothelium interactions in hepatic I/R injury.
  
  
  METHODS
  One hundred forty rats were randomized to 8 short-term or 12 long-term groups (n=7 each). A 30 min normothermic hepatic ischemia was induced by Pringle maneuver with a portocaval shunt. Animals were treated 60 min prior to ischemia with either no therapy, 0.1, 1.0, or 10 mg/kg b.w. bromelain i.v. In the short-term experiments, microcirculation was investigated 30 min after sham operation or ischemia using intravital microscopy. In the long-term experiments AST, ALT, and bradykinin levels were determined for 14 d after central venous catheter (CVC) placement only, sham operation, or ischemia. Additionally, apoptosis rate, Kupffer cell activation, endothelial cell damage, and eNOS expression were analyzed.
  
  
  RESULTS
  In sham-operated animals, treatment with 10 mg/kg b.w. bromelain led to a disturbed microcirculation with increased leukocyte adherence, apoptosis rate, Kupffer cell activation, and endothelial cell damage. Six h after CVC placement and administration of 10 mg/kg b.w. bromelain, AST and ALT levels were significantly increased. After I/R, rats treated with 0.1 mg/kg b.w. bromelain showed an improved microcirculation, reduction in leukocyte adhesion, apoptosis rates, Kupffer cell activation and endothelial cell damage, increased eNOS expression, and significantly lower AST levels compared with untreated animals.
  
  
  CONCLUSIONS
  Bromelain represents a novel approach to the treatment of hepatic I/R injury with a limited therapeutic window.
authors.affiliation: Surgical Research, Department of General Surgery, Muenster University Hospital Muenster, Germany. bahder@uni-muenster.de
authors.forename: Ralf
authors.initials: R
authors.lastname: Bahde
authors.forename: Daniel
authors.initials: D
authors.lastname: Palmes
authors.forename: Evgeni
authors.initials: E
authors.lastname: Minin
authors.forename: Udo
authors.initials: U
authors.lastname: Stratmann
authors.forename: Ricarda
authors.initials: R
authors.lastname: Diller
authors.forename: Jörg
authors.initials: J
authors.lastname: Haier
authors.forename: Hans-Ullrich
authors.initials: HU
authors.lastname: Spiegel
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000097:blood; D001963:Bromelains / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D007150:Immunohistochemistry; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007728:Kupffer Cells / Q000187:drug effects; D008102:Liver Circulation / Q000187:drug effects*; D008853:Microscopy; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016207:Cytokines; D001963:Bromelains; D001920:Bradykinin