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Cannabinoid‐2 receptor mediates protection against hepatic ischemia/reperfusion injury
Author(s) -
Batkai Sandor,
OseiHyiaman Douglas,
Pan Hao,
ElAssal Osama,
Rajesh Mohanraj,
Mukhopadhyay Partha,
Hong Feng,
HarveyWhite Judith,
Jafri Anjum,
Haskó Gyorgy,
Huffman John W.,
Gao Bin,
Kunos George,
Pacher Pál
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-7451com
Subject(s) - endocannabinoid system , cannabinoid , cannabinoid receptor , proinflammatory cytokine , liver injury , receptor , reperfusion injury , chemistry , cannabinoid receptor type 2 , inflammation , tumor necrosis factor alpha , pharmacology , ischemia , immunology , medicine , biochemistry , agonist
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 hepa‐tocytes, Kupffer, and endothelial cells. The I/R‐in‐duced 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‐1a and MIP‐2 levels, tissue lipid peroxidation, and expression of adhesion molecule ICAM‐1 in vivo. JWH133 also attenuates the TNF‐a‐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., Hasko, G., Huffman, J. W., Gao, B., Kunos, G., Pacher, P. Cannabi‐noid‐2 receptor mediates protection against hepatic ischemia/reperfusion injury. FASEB J. 21, 1788–1800 (2007)