The role of the endocannabinoid system in liver 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‐arachidonoyl glycerol (2‐AG), which originate from hepatocytes, Kupffer and endothelial cells. Concomitant activation of CB2 cannabinoid receptors by endocannabinoids protects against I/R damage by decreasing inflammatory cell infiltration, tissue and serum TNFá, MIP‐1á and MIP‐2 levels, and tissue expression of ICAM‐1, as indicated by the increased I/R‐induced tissue damage and pro‐inflammatory phenotype in CB2−/− mice or following CB2 blockade in wild‐type mice. We also show that the CB1 cannabinoid receptor agonist, HU‐210, reduces ischemic damage by centrally mediated hypothermia, while CB1 receptor knockout mice show increased I/R‐induced tissue damage and pro‐inflammatory phenotype following injury. Surprisingly, in contrast to knockouts, the CB1 receptor antagonists SR141716 and AM251 show a tendency to reduce ischemic damage. These findings indicate that targeting CB2 and CB1 cannabinoid receptors may represent a novel protective strategy in hepatic I/R injury. Furthermore, CB1 antagonists might exert additional anti‐inflammatory effects not mediated via CB1 receptors.