Pivotal Advance: Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis

Mohanraj Rajesh, Hao Pan, Partha Mukhopadhyay, Sándor Bátkai, Douglas Osei-Hyiaman, György Haskó, Lucas Liaudet, Bin Gao, Pál Pacher

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Abstract

In this study, we have investigated the role of the cannabinoid CB 2 (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-α-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-α, MIP-1α, 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-α-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 CB 2 receptor agonists may represent a novel, protective strategy against I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis.

Original languageEnglish
Pages (from-to)1382-1389
Number of pages8
JournalJournal of Leukocyte Biology
Volume82
Issue number6
DOIs
Publication statusPublished - Dec 1 2007

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Keywords

  • Adhesion
  • Endothelial activation
  • Inflammation
  • TNF-α

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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