Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury
Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury
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DOI：
10.1096/fj.06-7451com
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发表时间：
2007-06-01
期刊：
影响因子：
4.8
通讯作者：
Pacher, Pal
中科院分区：
文献类型：
--
作者：
Batkai, Sandor;Osei-Hyiaman, Douglas;Pacher, Pal
肝脏缺血再灌注（I/R）损伤仍然是肝脏手术或移植后的致命并发症。我们已经研究了参与内源性大麻素系统在肝I/R损伤使用在体内小鼠模型。在这里，我们报告说，I/R触发内源性大麻素anandamide和2-arachidonoylglycerol，这源于肝细胞，枯否细胞和内皮细胞的肝脏水平的几倍增加。I/R诱导的组织内源性大麻素水平升高与肝损伤程度和血清TNF-α、MIP- 1 α和MIP- 2水平呈正相关。此外，肝细胞短暂暴露于各种氧化剂（H2 O2和过氧亚硝酸盐）或炎症刺激（内毒素和TNF-α）也会增加内源性大麻素水平。通过JWH 133激活CB 2大麻素受体，通过降低体内炎性细胞浸润、组织和血清TNF-α、MIP-1 α和MIP- 2水平、组织脂质过氧化和粘附分子ICAM- 1的表达来保护I/R损伤。JWH 133还在体外减弱TNF-α诱导的人肝窦内皮细胞（HLSEC）中ICAM-1和VCAM- 1的表达以及人嗜中性粒细胞与HLSEC的粘附。与CB 2受体活化的保护作用一致，CB 2-/-小鼠发展增加的I/R诱导的组织损伤和促炎表型。这些研究结果表明，氧化/亚硝化应激和炎症刺激可能会触发内源性大麻素的产生，并表明，针对CB 2大麻素受体可能是一种新的保护策略，对I/R损伤。我们还证明CB 2-/-小鼠具有正常的血流动力学特征。Batkai，S.，Osei-Hyiaman，D.，潘，H.，El-Assal，O.，Rajesh，M.，Mukhopadhyay，P.，Hong，F.，Harvey-White，J. Jafri，A.，Hasko，G.，霍夫曼，J.W.，Gao，B.，Kunos，G.，Pacher，P. 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- 1 alpha, 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-1 alpha 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.-Batkai, 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. Cannabinoid-2 receptor mediates protection against hepatic ischemia/ reperfusion injury.