Endotoxin-induced liver damage in rats is minimized by beta 2-adrenoceptor stimulation.

C A Izeboud, K H N Hoebe, A F Grootendorst, S M Nijmeijer, A S van Miert, R R Witkamp, R J T Rodenburg

Department of Bioanalysis, TNO Pharma, 3700 AJ Zeist, The Netherlands. izeboud@pharma.tno.nl

Inflammation research : official journal of the European Histamine Research Society ... [et al.] 2004 Mar

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To investigate the effects of beta(2)-adrenoceptor (beta(2)-AR) stimulation on endotoxin-induced liver damage and systemic cytokine levels in rats. Standard male Wistar rats. 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. 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. 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. 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.

Citation

C A Izeboud, K H N Hoebe, A F Grootendorst, S M Nijmeijer, A S van Miert, R R Witkamp, R J T Rodenburg. Endotoxin-induced liver damage in rats is minimized by beta 2-adrenoceptor stimulation. Inflammation research : official journal of the European Histamine Research Society ... [et al.]. 2004 Mar;53(3):93-9