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

Abstract

Background & AimsIn 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 B4 (LTB4) is an endogenous agonist of TRPV1 and mediates pancreatitis.MethodsAcute 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 LTB4 biosynthesis). Pancreatic tissues and plasma were collected and analyzed.ResultsRetrograde 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 LTB4 by cultured pancreatic acinar cells; MK886 inhibited this process.ConclusionsAdministration of caerulein or intraductal bile acids in mice causes production of LTB4 by pancreatic acinar cells. This activates TRPV1 on primary sensory nerves to induce acute pancreatitis.

The Role of Transient Receptor Potential Vanilloid 1 in Common Diseases of the Digestive Tract and the Cardiovascular and Respiratory System

“…Previous studies have demonstrated that inflammatory damage can lead to the release of endogenous TRPV1 agonists in the pancreas, thereby activating TRPV1 in the primary sensory nerve, which in turn promotes the release of inflammatory neurotransmitters such as SP and CGRP. The above results indicate that TRPV1 receptor activation is associated with the production of pancreatic inflammation and pain (Shahid et al, 2015).…”

Piezo1 is a mechanically activated ion channel and mediates pressure induced pancreatitis

“…Surgery was performed as previously described 50 with the following modifications. Pressure experiments were conducted by injecting buffered (HEPES 10 mM, pH 7.6) isotonic saline solution into the pancreatic duct using a high performance PHD ultra-syringe I/W programmable pump with a pressure transducer APT300 Hg from Harvard Apparatus that was set to a range of 0–200 mm Hg.…”

“…The reaction was stopped by adding 4.3 mL of NaOH at 35 mM. The sample mixture was centrifuged for 15 min at 4 °C at 1900 × g 50 . The optical density (OD) of the supernate was measured at 620 nm.…”

“…Hematoxylin-and-eosin-stained tissues were imaged on an Olympus Vanox AHBS3 photomicroscope, with an Olympus DP70 digital camera, using a PlanApo ×10 objective. RNA isolation from acinar cells, reverse transcriptase, and real-time PCR procedures were also previously described 50 . RNAs were isolated using the RiboPure Kit (Invitrogen, catalog number AM1924) followed by DNase1 digestion (Invitrogen, catalog number AM1906).…”

Involvement of Neural Transient Receptor Potential Channels in Peripheral Inflammation

“…For example, mice injected with cerulean to induce acute pancreatic inflammation, display an increase in TRPV1 excitability and mRNA expression on NG and DRG neurons (126). Cerulean also leads to leukotriene B4 production by acinar pancreas cells, activating TRPV1 on sensory afferents (89). Treatment with capsazepine, a TRPV1 antagonist, was capable of reducing myeloperoxidase activity and histological severity of acute pancreatitis (127).…”