Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury.
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-alpha, MIP-1alpha, and MIP-2 levels. Furthermore, a brief exposure of hepatocytes to various oxidants (H2O2 and peroxynitrite) or inflammatory stimuli (endotoxin and TNF-alpha) also increases endocannabinoid levels. Activation of CB2 cannabinoid receptors by JWH133 protects against I/R damage by decreasing inflammatory cell infiltration, tissue and serum TNF-alpha, MIP-1alpha and MIP-2 levels, tissue lipid peroxidation, and expression of adhesion molecule ICAM-1 in vivo. JWH133 also attenuates the TNF-alpha-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 CB2 receptor activation, CB2-/- 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 CB2 cannabinoid receptors may represent a novel protective strategy against I/R injury. We also demonstrate that CB2-/- mice have a normal hemodynamic profile.
Bátkai
Sándor
S
Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892-9413, USA.
Osei-Hyiaman
Douglas
D
Pan
Hao
H
El-Assal
Osama
O
Rajesh
Mohanraj
M
Mukhopadhyay
Partha
P
Hong
Feng
F
Harvey-White
Judith
J
Jafri
Anjum
A
Haskó
György
G
Huffman
John W
JW
Gao
Bin
B
Kunos
George
G
Pacher
Pál
P
D000818:Animals; D001095:Arachidonic Acids / Q000032:analysis; D063385:Cannabinoid Receptor Modulators / Q000032:analysis / Q000096:biosynthesis; D004195:Disease Models, Animal; D063388:Endocannabinoids; D005989:Glycerides / Q000032:analysis; D006801:Humans; D007249:Inflammation; D008099:Liver / Q000737:chemistry; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D053284:Polyunsaturated Alkamides / Q000032:analysis; D043885:Receptor, Cannabinoid, CB2 / Q000502:physiology*; D015427:Reperfusion Injury / Q000209:etiology; D015854:Up-Regulation
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; C094503:glyceryl 2-arachidonate; C078814:anandamide