Mechanism Of Mast Cells Involved In Chronic Pancreatitis Pain

BackgroundChronic pancreatitis is characterized by inflammation,atrophy,fibrosis with progressive ductal changes,and functional changes that include variable exocrine and endocrine insufficiency and multiple patterns of pain.Clinical studies have reported that in chronic pancreatitis,the most common physician-identified etiologies were alcohol(45.8%)and idiopathic(24.3%).The most common individual pain pattern was described as severe pain and was reported in 45% of patients.The character of abdominal pain in these patients is highly variable,with some patients having severe daily pain whereas others have fleeting discomfort or are asymptomatic.Abdominal pain remains one of the most distress-ing symptoms of chronic pancreatitis.Pain represents the most common and difficult to control pain of chronic pancreatitis(CP),affecting individual life.Review covers the latest developments in the treatment options for chronic pancreatitis.Conventional treatment strategies and recent changes in the treatment of pain in patients with chronic pancreatitis are outlined.Thus,it is very important to control pain.The pathogenesis of abdominal pain in chronic pancreatitis is poorly understood.Pancreatic neuritis is a histopathological hallmark of pancreatic neuropathy and correlates to abdominal neuropathic pain sensation in chronic pancreatitis(CP).However,inflammatory cell subtypes that compose pancreatic neuritis and their correlation to the neuropathic pain syndrome in CP are yet unknown.Indeed,there is a considerable number of visceral painful disorders in which MC have been shown to be specifically enriched around intra-organ nerve fibers and correlate to the extent of pain sensation.The specific enrichment of MC around intrapancreatic nerves in neuropathic pain due to CP suggests the presence of MC induced visceral hypersensitivity in the pancreas.MC are resident immune cells in the GI tract,skin,lung,brain and other tissues and are classically known as mediators of type I hypersensitivity reactions to allergens or anaphylactic agents by releasing a large set of MC-derived degranulation products like histamine,serotonin,cytokines,prostaglandins,etc.These molecules corresponding receptors activated and sensitized peripheral neurons,causing pain and dysregulation of neuronal function.The objective of our study was to investigate the mechanism of mast cells in chronic pancreatitis pain.Methods1.By using toluidine blue staining of pancreas tissue,Compare of different expression of mast cells between normal pancreas and chronic pancreatitis.Building up a rat model of chronic pancreatitis,Mechanical pain and rat facial pain scale was measured.we administered mast cell stabilizer in chronic pancreatitis animal models and observed pain behavior.2.Immunofluorescence was used to detect PAR-2 receptors in pancreatic tissue between normal pancreas and chronic pancreatitis.Different expression by immunofluorescence and Western blot method was used to observe in DRG neurons between control group and chronic pancreatitis rats,including PAR-2,TRPV1 and NGF and its high affinity receptor TrkA.3.By Immunofluorescence double labeling TrkA receptor and PAR-2 receptor were detected in rat DRG neurons.By electrophysiological experiments in acutely isolated DRG neurons,the change in capsaicin current were observed,among control group,PAR-2 agonist group,NGF group and the PAR-2 agonist + NGF group.Results1.mast cells in pancreatic tissue was significantly increased in patients with chronic pancreatitis.Compared with control rats,the number of mast cells in the pancreatic tissue of chronic pancreatitis rat models was also significantly increased.When the rat model of chronic pancreatitis was administered mast cell stabilizers,abdominal pain relieved.2.We detected the expression of PAR-2 receptors in pancreatic tissues between normal pancreas and chronic pancreatitis.Immunofluorescence assay test under high-power microscopy results showed that the distribution of PAR-2 receptor was in the cytoplasm surrounding the nucleus,and PAR-2 expression in chronic pancreatitis tissue was higher than normal pancreas.Compared with control rats,PAR-2 receptor,TRPV1 receptors and NGF and its high affinity receptor TrkA receptor in DRG neurons were significantly increased in chronic pancreatitis rat model.3.PAR-2 receptor and TrkA receptor were co-expressed in DRG neurons of normal rats,and more importantly co-expressed cells were small-diameter neuron.With acute isolated DRG neurons,electrophysiological experiments found that,compared with the control group,the change in capsaicin current in PAR-2 agonist group and NGF group were significantly increased;Similarly,compared to the PAR-2 agonist group and NGF group,PAR-2 agonist + NGF group was significantly increased.Conclusion1.when administered mast cell stabilizers,abdominal pain relieved in chronic pancreatitis rat model.The results obtained in this study suggest that the systematic administration of ketotifen could represent an appropriate therapeutic strategy to prevent or reduce the pain induced by chronic pancreatitis.2.NGF produced by mast cells would act on its high affinity receptor TrkA located on nerve fibers,leading to pain.And studies suggest that PAR-2 receptor,TRPV1 receptors and NGF and its high affinity receptor TrkA is involved in the maintenance of mast cell hyperplasia and activation.3.Synergistic Role of PAR-2 and TrkA may participated in chronic pancreatic pain inducing by mast cells.