Protective Effect Of Wortmannin Against Severe Acute Pancreatitis In Rats And The Change Of Serum Proteinogram In Rats With Severe Acute Pancreatitis

Severe acute pancreatitis(SAP) accounts for taking 10%-25% of acute pancreatitis (AP) and its case fatality reaches up to 20%-30%. 60% of the dead case died at the first week and lung complication, such as acute respiratory distress syndrome, is the main reason for death. There are many theories about the pathogenesy of SAP, so far, the acknowledged theory includes: "trypsogen autodigestion", "calcium overload", "pancreas microcirculation disturbance", "inflammation and cytokine", "aversion of bacterium and endotoxin", etc. In recent years, the relationship between PI3K signal passageway and disease of pancreas obtained more and more attention. When PI3K signal passageway was activated, its product can cause further activation of the downstream factor, and recruit neutrophil to produce many kinds of inflammatory factor which lead to so-called "cytokine storm" and result in multi-organ damage. PI3K can activate trypsinogen by increasing the intra-cellular Ca²⁺ level to promote the development of pancreatitis. Our study use wortmannin, the depressantia of PI3K signal passageway to interfere SAP rats, and investigate its protective effect against SAP in rats; at the same time, we use two-dimensional electrophoresis to investigate the change of serum proteingram in rats, in order to further research on the serum inflammatory factor in SAP rats.AIM: To observe the protective and therapeutic effect of wortmannin, inhibitor of Phosphatidylinositol 3-kinase(PI3K), against SAP in rats and investigate its mechanism; use two-dimensional electrophoresis to investigate the change of proteingram in SAP rats.METHODS: Fifty-four SD rats were randomly divided into 5 groups: control group, SAP group, SAP+wortmannin group(n=18 per group), SAP model was induced by retrograde infusion of 50g/L sodium taurocholate into the biliopancreatic duct of rats. Serum level of tumor necrosis factor-alpha(TNF-α), serum level of amylase, myeloperoxidase(MPO) activity of pancreatic tissue and the protein content of bronchoalveolar lavage fluids(BALF) were evaluated; histopathology of lung and pancreas were studied, the serum proteingram in control group and SAP group are also compared.RESULTS: In SAP group, serum level of TNF-α, serum level of amylase, MPO activity of pancreatic tissues and the protein content of BALF were significantly elevated(P<0.01); the lung and pancreas injuries were gradually aggravated with disease progression. All the indicators of SAP+wortmannin group were also elevated as compared with control group, but still significantly decreased as compared with SAP group(P<0.01), there's no statistical difference between the two groups. All indicators of control group have no statistical difference either. There are many protein disparate points in serum proteingram of SAP rats as compared with that of healthy rats.CONCLUSION: Pretreatment with wortmannin could decrease the severity of pancreatitis rats. The mechanism may be include the inhibition on the activity of PI3K in pancreatic acinar cell, thus calcium overload is decreased and the activation of trypsinogen is inhibited in a certain extent; the inhibition on activation of PI3K in polymorphonuclear neutrophils(PMN), further more, on the activation of many kinds of inflammatory cells and on the release of TNF-αand other inflammatory factors. The many protein disparate points in serum proteingram indicate that many inflammatory cytokines participate in the development of SAP, and its specific mechanism still needs further research.