Leukotriene B4 Mediates Inflammation via TRPV1 in Duct Obstruction-induced Pancreatitis in Rats

Objectives—We tested the hypothesis that leukotriene B4 (LTB4) mediates pancreatic inflammation in rats via activation of the Transient Receptor Potential Vanilloid 1 (TRPV1). Methods—LTB4 or vehicle was administered to adult rats via celiac axis injection following pretreatment with the TRPV1 antagonist, capsazepine, or vehicle and the severity of subsequent pancreatitis was assessed by measuring pancreatic edema, myeloperoxidase (MPO) activity, and histological grading. In a second experiment, acute pancreatitis was induced by common pancreaticobiliary duct ligation (CPBDL). Six hours postoperatively, pancreatic tissue levels of LTB4 were determined by ELISA. Also, the effects of inhibition of LTB4 biosynthesis by pretreatment with the 5-lipoxygenase activating peptide (FLAP) inhibitor, MK-886, were determined. Results—Celiac axis administration of LTB4 significantly increased pancreatic edema and MPO activity, and produced histological evidence of pancreatic edema, neutrophil infiltration, and necrosis. Capsazepine pretreatment significantly reduced all inflammatory parameters in LTB4induced pancreatitis. Pancreatic tissue levels of LTB4 were significantly elevated in rats that underwent CPBDL compared to control rats. MK-886 pretreatment significantly inhibited pancreatic edema, histological damage, and pancreatic MPO concentrations. Conclusions—Common pancreaticobiliary duct obstruction causes an increase in pancreatic LTB4 concentrations that in turn mediates activation of TRPV1 resulting in acute pancreatitis.