title: Endotoxin-induced liver damage in rats is minimized by beta 2-adrenoceptor stimulation.
abstract: OBJECTIVE
  To investigate the effects of beta(2)-adrenoceptor (beta(2)-AR) stimulation on endotoxin-induced liver damage and systemic cytokine levels in rats.
  
  
  METHODS
  Standard male Wistar rats.
  
  
  METHODS
  A disease-model of lipopolysaccharide (LPS)-induced acute systemic inflammation was used. The beta(2)-selective AR agonist clenbuterol was administered before, during, and after LPS-challenge to investigate its effects on the acute inflammatory response and associated liver-failure.
  
  
  METHODS
  The following parameters have been measured in plasma: TNF alpha, IL-1 beta, IL-6, IL-10, AST, ALT, and Bilirubin. Liver histological examination was performed to look for changes in tissue morphology.
  
  
  RESULTS
  Administration of clenbuterol (p.o.) one hour before, or intravenous at the same time as LPS-challenge resulted in a marked reduction of plasma levels of TNF alpha, IL-1 beta, and IL-6. A change both in plasma-level and in time-concentration profile of the anti-inflammatory cytokine IL-10 was found. Clenbuterol minimized LPS-induced liver damage, as represented by significantly lowered concentrations of several parameters for liver-failure (AST, ALT, Bilirubin), and improved hepatic tissue morphology. Clenbuterol administration after LPS challenge failed to inhibit TNF alpha-release but reduced liver-damage. Simultaneous use of the beta(2)-AR antagonist propranolol augmented LPS-induced liver failure, suggesting a role of endogenous adrenoceptor-agonists in prevention of organ-failure during systemic inflammation.
  
  
  CONCLUSIONS
  The results indicate that a selective beta(2)-AR agonist might be used as an additional therapeutic agent in the clinic for the treatment of (acute) systemic inflammatory disorders in order to reduce or prevent subsequent liver failure.
authors.affiliation: Department of Bioanalysis, TNO Pharma, 3700 AJ Zeist, The Netherlands. izeboud@pharma.tno.nl
authors.forename: C A
authors.initials: CA
authors.lastname: Izeboud
authors.forename: K H N
authors.initials: KH
authors.lastname: Hoebe
authors.forename: A F
authors.initials: AF
authors.lastname: Grootendorst
authors.forename: S M
authors.initials: SM
authors.lastname: Nijmeijer
authors.forename: A S
authors.initials: AS
authors.lastname: van Miert
authors.forename: R R
authors.initials: RR
authors.lastname: Witkamp
authors.forename: R J T
authors.initials: RJ
authors.lastname: Rodenburg
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002976:Clenbuterol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007249:Inflammation / Q000517:prevention & control; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000097:blood; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000473:pathology*; D017093:Liver Failure / Q000517:prevention & control*; D008297:Male; D009994:Osmolar Concentration; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D002976:Clenbuterol; D004731:Endotoxins; D007375:Interleukin-1; D016753:Interleukin-10; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011433:Propranolol; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors