DECREASED MORTALITY OF SEVERE ACUTE-PANCREATITIS AFTER PROXIMAL CYTOKINE BLOCKADE

Objective This study determined the ability of interleukin-1 receptor antagonist (IL-1ra) to decrease the mortality of experimental acute pa ncreatitis. The response of the inflammatory cytokine cascade and its subsequent effects on pancreatic morphology were measured to determine the role of these peptides in mediating pancreatic injury. Summary Ba ckground Data Previous studies have shown that proinflammatory cytokin es are produced in large amounts during acute pancreatitis and that bl ockade at the level of the IL-1 receptor significantly decreases intri nsic pancreatic damage. The subsequent effect on survival is not known . Methods A lethal form of acute hemorrhagic necrotizing pancreatitis was induced in young female mice by feeding a choline-deficient, ethio nine supplemented (CDE) diet for 72 hours. For determination of mortal ity, the animals were divided into 3 groups of 45 animals each: contro l subjects received. 100/mu L normal saline intraperitoneally every 6 hours for 5 days; IL-1ra early mice received recombinant interleukin-1 receptor antagonist 15 mg/kg intraperitoneally every 6 hours for 5 da ys beginning at time O; IL-1ra late mice received IL-1ra 15 mg/kg intr aperitoneally every 6 hours for 3.5 days beginning 1.5 days after intr oduction of the CDE diet. A parallel experiment was conducted simultan eously with a minimum of 29 animals per group, which were sacrificed d aily for comparisons of serum amylase, lipase, IL-1, IL-6, tumor necro sis factor-alpha, IL-1ra, pancreatic wet weight, and blind histopathol ogic grading. Results The 10-day mortality in the untreated control gr oup was 73%. Early and late IL-1 ra administration resulted in decreas es of mortality to 44% and 51%, respectively (both p < 0.001). interle ukin-1 antagonism also was associated with a significant attenuation i n the rise in pancreatic wet weight and serum amylase and lipase in bo th early and late IL-1ra groups (all p < 0.05). All control animals de veloped a rapid elevation of the inflammatory cytokines, with maximal levels reached on day 3. The IL-1ra-treated animals, however, demonstr ated a blunted rise of these mediators (all p < 0.05). Blind histologi c grading revealed an overall decrease in the severity of pancreatitis in those animals receiving the antagonist. Conclusions Early dr late blockade of the cytokine cascade at the level of the IL-1 receptor sig nificantly decreases the mortality of severe acute pancreatitis. The m echanism by which this is accomplished appears to include attenuation of systemic inflammatory cytokines and decreased pancreatic destructio n.