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Endotoxin-induced liver damage in rats is minimized by β2- adrenoceptor stimulation

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Author: Izeboud, C.A. · Hoebe, K.H.N. · Grootendorst, A.F. · Nijmeijer, S.M. · Miert, A.S. van · Witkamp, R.F. · Rodenburg, R.J.T.
Type:article
Date:2004
Institution: TNO Voeding
Source:Inflammation Research, 3, 53, 93-99
Identifier: 237663
doi: doi:10.1007/s00011-003-1228-y
Keywords: Biology Pharmacology · Physiological Sciences · Adrenoceptor agonists · Cytokines · Endotoxemia · Immunopharmacology · Liver-failure · alanine aminotransferase · aspartate aminotransferase · beta adrenergic receptor · bilirubin · clenbuterol · cytokine · endotoxin · interleukin 10 · interleukin 1beta · interleukin 6 · lipopolysaccharide · propranolol · tumor necrosis factor alpha · animal model · animal tissue · article · controlled study · enzyme linked immunosorbent assay · liver failure · liver injury · male · nonhuman · rat · Adrenergic beta-Agonists · Adrenergic beta-Antagonists · Alanine Transaminase · Animals · Aspartate Aminotransferases · Clenbuterol · Endotoxins · Inflammation · Interleukin-1 · Interleukin-10 · Interleukin-6 · Lipopolysaccharides · Liver · Liver Failure · Male · Osmolar Concentration · Propranolol · Rats · Rats, Wistar · Tumor Necrosis Factor-alpha

Abstract

Objective and Design: To investigate the effects of β2- adrenoceptor (β2-AR) stimulation on endotoxin-induced liver damage and systemic cytokine levels in rats. Subjects: Standard male Wistar rats. Treatment: A disease-model of lipolysaccharide (LPS)-induced acute systemic inflammation was used. The β2-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: TNFα, IL-1β, 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 TNFα, IL-1β, 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 TNFα-release but reduced liver-damage. Simultaneous use of the β2-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 β2-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.