Effect of NF-κB on gut-original endotoxemia converting edematous pancreatitis to necrotizing pancreatitis in mice

Objective To investigate the possible role of nuclear factor-kappa B(NF-κB)in gut-original endotoxemia converting acute edematous pancreatitis(AEP) to acute necrotizing pancreatitis(ANP)in mice, anti-oxidant pyrrolidine dithiocarbamate(PDTC)was applied in an attempt to inhibit the activity of NF-κB. Methods Eighty-five C57BL/6 mice were assigned to 5 groups randomly, including normal control,LPS, AEP, AEP plus LPS and AEP?LPS plus PDTC. AEP in mice was induced by the intraperitoneal injections of cerulein with a dosage of 50 μg/kg at hourly interval for seven times. LPS was administrated via a gastric tube with a dosage of 5 mg/kg at 6 h following the first cerulein or saline injection. PDTC was injected intraperitoneally at a dose of 100 mg/kg.Serum amylase and LDH activities were measured at 12 h,24 h,48 h and 5 d.Pathological alteration in pancreas was studied. Expressions of Mac-1 (CD11b/CD18), P-selectin, E-selectin and ICAM-1 were evaluated by using inmmunohistochemical procedures. Expressions of pancreatic cytokine genes were determined by means of Southern blotting.Results LPS alone didn't develop either morphological changes or biochemical alterations. Cerulein induced a typical changes of AEP in mice. Cerulein-induced AEP challenged by LPS could cause marked parenchymal necrosis and hemorrhage in pancreas, and significant increments of serum amylase and LDH activities. ANP in mice pretreated with PCTC resulted in amelioration of pancreatic histology and decline of serum amylase and LDH activities. Expressions of Mac-1, P-selectin, E-selectin and ICAM-1 in pancreas were weakened. Cytokine genes including TNF-α, IL-1β were also downregulated.Conclusion This study suggested that gut-original endotoxemia,which could not induce pancreatic injury per se,could transit AEP into ANP in mice.Over-stimulation of neutrophils and releasing of pro-inflammatory mediators would be contributing factors during this process.PDTC could reduce the severity of pacreatitis by inhibiting the activity of NF-κB,blocking the endotoxic signal pathway and peventing from the further cytokines activation.It suggests that NF-κB plays an intermediating role in gut-original endotoxemia converting AEP to ANP in mice.