Journal
JOURNAL OF LEUKOCYTE BIOLOGY
Volume 82, Issue 6, Pages 1382-1389Publisher
WILEY
DOI: 10.1189/jlb.0307180
Keywords
endothelial activation; adhesion; inflammation; TNF-alpha
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Funding
- Intramural NIH HHS [Z01 AA000375-02, Z99 AA999999] Funding Source: Medline
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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-alpha-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-alpha, MIP-1 alpha, 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-alpha-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.
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