Tumor necrosis factor-alpha (TNFα) is postulated to be a mediator of the systemic complications associated with acute pancreatitis. Neutralization of TNFα with monoclonal antibody ameliorates the morbidity and mortality associated with acute pancreatitis in a rat model. Although high levels of TNFα are measurable in peripheral blood in acute pancreatitis, specific sites of TNFα production in this disease have not been described. In this study we show that induction of pancreatitis causes up-regulation of TNFα messenger RNA (mRNA) at a distant organ site, the spleen. Hemisplenectomies were performed in male Sprague-Dawley rats prior to induction of pancreatitis by pancreatic duct infusion of artificial bile. Completion hemisplenectomies were then performed at 30 min, 1 hr, and 2 hr after pancreatitis induction. Quantitation of TNFα mRNA in the hemispleens before and after pancreatitis using a semiquantitative reverse transcriptase-polymerase chain reaction method revealed an 80-fold increase in amount of TNFα mRNA by 2 hr after induction of pancreatitis. By contrast, control rats receiving a sham operation showed no significant increase in TNFα mRNA expression after infusion of the pancreatic duct with saline. The increase in TNFα mRNA production was associated with increased serum TNFα product levels and was independent of endotoxin. We conclude that severe acute pancreatitis in the rat model is associated with significant up-regulation of TNFα mRNA in splenic mononuclear cells. These data provide evidence that the local events of acute pancreatitis can induce up-regulation of TNFα mRNA at a distant site and suggest a possible mechanism of pathogenesis of the systemic manifestations of this disease.
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