Antagonism of the cannabinoid CB-1 receptor protects rat liver against ischemia-reperfusion injury complicated by endotoxemia
| Autor: | A. Principe, C Mastroleo, Paolo Caraceni, T. Croci, Ferdinando Giannone, Juan Carlos Cutrin, Maria-Giulia Perrelli, Anna Maria Pertosa, Marco Domenicali, Mauro Bernardi, Franco Trevisani, Ignazio Grattagliano |
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| Přispěvatelé: | Caraceni P, Pertosa AM, Giannone F, Domenicali M, Grattagliano I, Perrelli MG, Principe A, Mastroleo C, Cutrin J, Trevisani F, Croci T, Bernardi M. |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Lipopolysaccharides
Male Necrosis Lipopolysaccharide RIMONABANT Drug Evaluation Preclinical Blood Pressure Pharmacology Rats Sprague-Dawley chemistry.chemical_compound Piperidines Receptor Cannabinoid CB1 Rimonabant medicine Animals SOCS3 Interleukin 6 Liver injury biology Suppressor of cytokine signaling 1 business.industry CYTOKINES Gastroenterology ENDOCANNABINOIDS Alanine Transaminase medicine.disease Endotoxemia Rats Liver Neutrophil Infiltration chemistry Reperfusion Injury Immunology HEPATIC ISCHEMIA-REPERFUSION INJURY biology.protein Pyrazoles lipids (amino acids peptides and proteins) ENDOTOXIN medicine.symptom business Reperfusion injury Liver Circulation medicine.drug |
| Popis: | Background/aim: Endotoxaemia can complicate hepatic ischaemia–reperfusion (IR) injury. Endocannabinoids appear to modulate the haemodynamic alterations and cytokine response induced by lipopolysaccharide (LPS). Thus, we aimed to determine the effect of the endocannabinoid CB1-receptor antagonist Rimonabant in a model of hepatic IR injury complicated by endotoxaemia. Methods: Sprague–Dawley rats pre-treated with Rimonabant 3 or 10 mg/kg or vehicle underwent partial hepatic IR and lipopolysaccharide (LPS) injection at reperfusion. Liver injury was evaluated by serum alanine aminotransferase (ALT) and necrotic-cell count. The inflammatory response was investigated by assessing hepatic neutrophil infiltration, tumour necrosis factor α (TNFα), interferon γ (IFNγ), interleukin 6 (IL6), and suppressor of cytokine signalling (SOCS) 1 and SOCS3 gene expression by real-time polymerase chain reaction (RT-PCR). Systolic blood pressure and hepatic blood flow were measured as haemodynamic parameters. Finally, lipid peroxidation, glutathione status, and immunoreactive CB1 receptor expression in the liver were also determined. Results: Liver injury and neutrophil infiltration occurring in the late-phase of LPS-enhanced IR were significantly reduced by CB1-receptor antagonism. Rimonabant-treated rats showed significantly higher gene expression of IFNγ, IL6, SOCS1 and SOCS3 in “early” reperfusion, while that of TNFα was reduced. These findings were associated with increased STAT3 phosphorylation. Furthermore, CB1-receptor antagonism significantly improved the oxidative injury and haemodynamic alterations occurring during reperfusion in untreated rats. Finally, CB1-receptor immunoreactivity was upregulated early after reperfusion. Conclusions: This study demonstrates that CB1-receptor antagonism protects the liver against LPS-enhanced IR injury by interfering with the inflammatory response that causes the late, neutrophil-dependent phase of reperfusion injury, although the prevention of the transient endotoxin-related hypotension occurring early during reperfusion may be also involved. |
| Databáze: | OpenAIRE |
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