LIPOPOLYSACCHARIDE-INDUCED DESENSITIZATION TO PANCREATIC EDEMA FORMATION IN RAT CERULEIN PANCREATITIS

Previously we reported that prior administration of lipopolysaccharide (LPS) mitigates subsequently produced cerulein (Cn) pancreatitis. To clarify the mechanism further, the pathological features of Cn pancrea titis were examined in detail after treating rats with very low doses of LPS. LPS pretreatment reduced the formation of pancreatic edema dur ing Cn pancreatitis in a dose-and time-dependent manner. in contrast, the elevation of serum amylase and the histological findings, includin g acinar cell vacuolization and infiltration of inflammatory cells, we re not affected. The lowest dose of LPS, 500 ng/kg, was sufficient to inhibit pancreatic edema formation completely. LPS at a dose of 5 mu g /kg was fully effective when it was given from 30 min to 12 h before t he induction of pancreatitis. Pretreatment with tumor necrosis factor- alpha (TNF-alpha) inhibited the pancreatic edema in a manner similar t o that of LPS. Moreover, the inhibitory effect of LPS was partially at tenuated by the administration of anti-TNF-alpha antibody before the i njection of LPS. Actinomycin D (0.5 mg/kg) abolished the effect of LPS , whereas cycloheximide (0.5 mg/kg) given alone reduced pancreatic ede ma formation during pancreatitis. From these results, it was concluded that very low doses of LPS can induce, partially via TNF-alpha, a sta te refractory to pancreatic edema formation during Cn pancreatitis, an d this phenomenon seems to be regulated at the transcriptional level.