Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury Sándor Bátkai * , Douglas Osei-Hyiaman * , Hao Pan * , Osama El-Assal * , Mohanraj Rajesh * , Partha Mukhopadhyay * , Feng Hong * , Judith Harvey-White * , Anjum Jafri * , György Haskó † , John W. Huffman ‡ , Bin Gao * , George Kunos * and Pál Pacher * ,1 * 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 ‡ Howard L. Hunter Chemistry Laboratory, Clemson University, Clemson, South Carolina, USA 1 Correspondence: Section on Oxidative Stress and Tissue Injury, Laboratory of Physiologic Studies, National Institutes of Health/NIAAA, 5625 Fishers Lane, MSC-9413, Bethesda, Maryland 20892-9413, USA. E-mail: pacher@mail.nih.gov Hepatic ischemia-reperfusion (I/R) injury continues to be a fatal complication that can follow liver surgery or transplantation. We have investigated the involvement of the endocannabinoid system in hepatic I/R injury using an in vivo mouse model. Here we report that I/R triggers several-fold increases in the hepatic levels of the endocannabinoids anandamide and 2-arachidonoylglycerol, which originate from hepatocytes, Kupffer, and endothelial cells. The I/R-induced increased tissue endocannabinoid levels positively correlate with the degree of hepatic damage and serum TNF-α, MIP-1α, and MIP-2 levels. Furthermore, a brief exposure of hepatocytes to various oxidants (H 2 O 2 and peroxynitrite) or inflammatory stimuli (endotoxin and TNF-α) also increases endocannabinoid levels. Activation of CB 2 cannabinoid receptors by JWH133 protects against I/R damage by decreasing inflammatory cell infiltration, tissue and serum TNF-α, MIP-1α and MIP-2 levels, tissue lipid peroxidation, and expression of adhesion molecule ICAM-1 in vivo . JWH133 also attenuates the TNF-α-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) and the adhesion of human neutrophils to HLSECs in vitro . Consistent with the protective role of CB 2 receptor activation, CB 2 –/– mice develop increased I/R-induced tissue damage and proinflammatory phenotype. These findings suggest that oxidative/nitrosative stress and inflammatory stimuli may trigger endocannabinoid production, and indicate that targeting CB 2 cannabinoid receptors may represent a novel protective strategy against I/R injury. We also demonstrate that CB 2 –/– mice have a normal hemodynamic profile.—Bátkai, S., Osei-Hyiaman, D., Pan, H., El-Assal, O., Rajesh, M., Mukhopadhyay, P., Hong, F., Harvey-White, J., Jafri, A., Haskó, G., Huffman, J. W., Gao, B., Kunos, G., Pacher, P. Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. Key Words: endocannabinoids • anandamide • 2-arachidonoylglycerol • peroxynitrite • oxidative stress

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