Timing of tumor necrosis factor antagonism is critical in determining outcome in murine lethal acute pancreatitis

Abstract

Tumor necrosis factor (TNF) is produced in large amounts within the pancreas, lungs, and liver during severe acute pancreatitis and is believed to mediate many of the detrimental consequences typical of this disease. Investigations into the benefit of TNF antagonism have suggested that TNF may also mediate processes that are protective to the host. With the hypothesis that timing plays a role in these dissenting views, TNF was antagonized either prophylactically or therapeutically with a recombinant form of the soluble type I TNF receptor (TNFbp) during a lethal model of necrotizing pancreatitis induced by feeding a choline-deficient diet. Mortality was determined for 10 days in 390 female mice divided into three groups: control, TNFbp early (time, 0 to 5 days), and TNFbp late (time, 1.5 to 5 days). Pancreatitis severity and cytokine production were assessed daily. Animals in the control group had a 75% mortality rate that was significantly decreased by prophylactic TNF blockade (64%, p < 0.05). Delaying TNF antagonism until serum cytokines were elevated and pancreatitis was manifest decreased mortality to 42% (p < 0.001 versus control, p < 0.01 versus early). Early and late TNF blockade decreased pancreatic edema and serum amylase, lipase, interleukin-1, and interleukin-6 (all p < 0.05) but not TNF. Late antagonism typically resulted in the greatest attenuation of all these parameters. Blockade of TNF by the administration of a soluble TNF receptor attenuates the severity of pancreatitis, decreases the production of associated inflammatory cytokines, and significantly improves survival. Delaying antagonism until pancreatitis is manifest and circulating cytokines are elevated but not yet maximal appears to be more protective than simple prophylactic TNF antagonism.