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Michler, Thomas (2010): Die Rolle von Cannabinoid 2 (CB2)-Rezeptoren bei der akuten Pankreatitis: Untersuchungen am Mausmodell. Dissertation, LMU München: Medizinische Fakultät



BACKGROUND: The endocannabinoid system (ECS) consists of the cannabinoid receptors 1 (CB1) and 2 (CB2), endogenous ligands (lipids) and endocannabinoid-degrading mechanisms. To date the best characterized endogenous cannabinoids are anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG). Both act as agonists on CB1 and CB2-receptors. Activation of CB2-receptors results in anti-inflammatory and analgesic effects, two characteristics which seem beneficial for treatment of acute pancreatitis. Furthermore, the activation of the MAP-kinases p38 and JNK by CB2-receptors has been described in other tissues. These two intra-cellular signaling-cascades have been shown to be involved in the early acinar events which lead to acute pancreatitis. Our aim was to examine the role of CB2-receptors in the pathophysiology of acute pancreatitis and the potential involvement of p38 and JNK in mediating the effects of their activation. Also, we looked at the therapeutic potential of administration of synthetic CB2-agonists. METHODS: Pancreatitis was induced by six hourly intra-peritoneal injections of cerulein (50µg/kg bw) in wild-type C57/bl and MK2 -/- mice. JWH133, a synthetic and specific CB2-agonist, or AM 630, a specific CB2 receptor antagonist, was administered 30 min prior to the first cerulein injection. Expression and distribution of CB2-receptors in pancreatic tissue was examined by RT-quantitative PCR, western blotting and immunohistochemistry. Severity of pancreatitis was determined by measuring serum amylase, IL-6 levels, trypsinogen activation, MPO activity and histological examinations. Pancreatic lysates were investigated by western blotting using phospho specific antibodies against p38 and JNK. RESULTS: Cannabinoid 2-receptors are expressed on acinous cells and other cell types of mouse pancreas. In state of acute pancreatitis an up-regulation and also an increased activation through endogenous ligands can be observed which leads to an attenuation of the pathology. This effect can be therapeutically exploited by administration of a synthetic CB2-agonist. Correlating to the protective effects, an increased intra-acinous activation of p38 and an inhibition of JNK can be observed. The known protective effects of p38 are mediated through activation of the kinase MK2 which again activates HSP27. Experiments in MK2 -/- mice show that at least the reduction of IL-6 levels and MPO activity are dependent on this pathway. Since pro-inflammatory cytokines like IL-6 are known to activate JNK in acinous cells, the observed inhibition of JNK by CB2-receptor activation might indirectly be mediated by MK2-dependend reduction of these cytokines.