Acinar Cell Production of Leukotriene B4 Contributes to Development of Neurogenic Pancreatitis in Mice

Background & Aims In the pancreas, activation of primary sensory nerves through the transient receptor potential vanilloid-1 (TRPV1) ion channel contributes to the early stages of development of pancreatitis. Little is known about the mechanism by which this occurs. We investigated whether leukotriene B 4 (LTB 4 ) is an endogenous agonist of TRPV1 and mediates pancreatitis. Methods Acute inflammation was induced in the pancreata of Trpv1 −/− mice and their wild-type littermates by retrograde infusion of the main pancreatic duct with 2% sodium taurocholate (NaT) or intraperitoneal injections of caerulein. Mice were also given injections of resiniferatoxin (an excitotoxin that desensitizes TRPV1) or MK886 (a drug that inhibits LTB 4 biosynthesis). Pancreatic tissues and plasma were collected and analyzed. Results Retrograde perfusion of the main pancreatic ducts of wild-type mice with NaT caused severe acute pancreatitis; the severity was reduced by coadministration of resiniferatoxin. Trpv1 −/− mice developed a less severe pancreatitis after NaT administration compared with controls. Administration of MK886 before perfusion with NaT also significantly reduced the severity of pancreatitis in wild-type mice. Pancreatic tissues from mice given NaT had a marked increase in the level of 5-lipoxygenase immunoreactivity specifically in acinar cells. Bile acid and caerulein induced secretion of LTB 4 by cultured pancreatic acinar cells; MK886 inhibited this process. Conclusions Administration of caerulein or intraductal bile acids in mice causes production of LTB 4 by pancreatic acinar cells. This activates TRPV1 on primary sensory nerves to induce acute pancreatitis.