Development of therapy directed at cell signalling abnormalities in experimental acute pancreatitis

• Main Author: Huang, Wei
• Published: University of Liverpool 2011
• Subjects: 616.37
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.569794

Acute pancreatitis remains a challenging disease because of incomplete understanding of its pathobiology and the absence of an effective specific therapy. To address these difficulties, experimental animal models are indispensable. Recent research has identified the key role of fatty acid ethyl esters in the pathogenesis of alcohol-induced acute pancreatitis, but to date there is no satisfactory experimental model. Since cell signalling abnormalities, including excessive intracellular release of calcium and/or reactive oxygen species (ROS) and induction of the mitochondrial permeability transition pore (MPTP) have been demonstrated to play a pivotal role in acute pancreatitis, targeting these pathways could either prevent this disease completely or ameliorate its severity. Such therapies require preliminary assessment in experimental models. A novel acute alcoholic pancreatitis model (F AEE-AP) was established by two concomitant administrations of ethanol (1.35 g/kg) and palmitoleic acid (80 or 150 mg/kg) at 1 h apart. 4-methylpyrazole, a non-oxidative ethanol metabolism pathway inhibitor, significantly increased the necrosis histopathological score of the pancreas, whereas 3-benzyl-6-chloro-2- pyrone, a F AEE synthase inhibitor, significantly decreased the severity of FAEE-AP. Bis-(4-nitrophenol) phosphate, an FAEE hydrolase inhibitor, did not show any significant protective effect against F AEE-AP. The inositol trisphosphate receptor inhibitor caffeine and its metabolites were investigated in mice with acute pancreatitis induced by either 7 or 12 injection of caerulein (50 ug/kg/h; CER-AP) or by infusion of 50 III taurolithocholic acid 3-sulphate (TLC-S, 3 mM; TLCS-AP). Caffeine (25 mg/kg/h) significantly reduced severity markers of pancreatitis in both CER-AP and TLCS-AP, an effect that might be due to inhibition of inositol triphosphate receptor, attenuation of endoplasmic reticulum stress and/or phosphodiesterase inhibition. The caffeine metabolites theophylline and paraxanthine however did not appear to be protective against CER-AP. Manipulation of ROS by menadione (an oxidant inducer), 2,4-dimethoxy- 2-methylnaphthalene (a non-cycling analogue of menadione) and n- acetyl cysteine (an antioxidant) in both CER-AP and TLCS-AP provided paradoxical results. Cyclophilin D knockout mice, which are resistant to formation of the MPTP, had significantly reduced histopathological scores and severity markers tested compared to wild type mice in FAEE-AP. The cyclophilin D inhibitor cyc1osporine A (l0 mg/kg) did not show a significantly protective effect in CER-AP, while its non-immunosuppressive analogue D-3-methyl-Ala-4-ethyl-Val-CyA (Debio-025, 10-100 mg/kg) significantly reduced histopathological scores and severity marker of CER-AP with the most marked effect at 10 mg/kg. These data suggest that inhibition of cytosolic and mitochondrial calcium overload could be effective strategies in the prophylaxis and/or treatment of acute pancreatitis.