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Published online before print July 25, 2007
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* Sections on Oxidative Stress Tissue Injury and
Liver Biology, Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA;
Department of Surgery, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA; and
Department of Intensive Care Medicine, University Hospital, Lausanne, Switzerland
1Correspondence: Section on Oxidative Stress and Tissue Injury, Laboratory of Physiologic Studies, National Institutes of Health/NIAAA, 5625 Fishers Lane, MSC-9413, Bethesda, MD 20892-9413, USA. E-mail: pacher{at}mail.nih.gov
ABSTRACT
In this study, we have investigated the role of the cannabinoid CB2 (CB2) receptor in an in vivo mouse model of hepatic ischemia/reperfusion (I/R) injury. In addition, we have assessed the role of the CB2 receptor in TNF-
-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and in the adhesion of human neutrophils to HLSECs in vitro. The potent CB2 receptor agonist HU-308, given prior to the induction of I/R, significantly attenuated the extent of liver damage (measured by serum alanine aminotransferase and lactate dehydrogenase) and decreased serum and tissue TNF-, MIP-1, and MIP-2 levels, tissue lipid peroxidation, neutrophil infiltration, DNA fragmentation, and caspase 3 activity. The protective effect of HU-308 against liver damage was also preserved when given right after the ischemic episode. HU-308 also attenuated the TNF--induced ICAM-1 and VCAM-1 expression in HLSECs, which expressed CB2 receptors, and the adhesion of human neutrophils to HLSECs in vitro. These findings suggest that selective CB2 receptor agonists may represent a novel, protective strategy against I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis.
Key Words: endothelial activation • adhesion • inflammation • TNF-
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J. Leukoc. Biol. 2007 82: 1390-1392.
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