INTERLEUKIN-1 RECEPTOR ANTAGONIST DECREASES SEVERITY OF EXPERIMENTAL ACUTE-PANCREATITIS

Background. Fulminant acute pancreatitis is a disease of complex origi n that results in activation of several of the proinflammatory cytokin es. Because interleukin-1 (IL-1) is an integral early component of the acute inflammatory process, the use of an IL-1 receptor antagonist (I L-1ra) was investigated in experimental acute Pancreatitis to determin e the therapeutic potential of proximal cytokine blockade and to furth er establish the role of inflammatory cytokines in the pathogenesis of acute pancreatitis. Methods. IL-1ra was administered in escalating do ses either before or after acute edematous, necrotizing pancreatitis w as induced in adult male mice by injection of cerulein. The severity o f pancreatitis was quantified by serum amylase, lipase, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) levels, pancreatic wet weight, and blinded histologic grading. Results. Administration o f medium (10 mg/kg) and high (100 mg/kg) doses of IL-1ra either before or after the induction of pancreatitis significantly decreased the ex pected rise in pancreatic wet weight, lipase, IL-6, and ThF-alpha (all , p < 0.01). Serum amylase was significantly reduced when IL-1ra was a dministered in either dosage before (p < 0.05), but not after, inducti on of pancreatitis. Pancreatic edema, necrosis, and inflammatory cell infiltrate were significantly diminished (p < 0.05) by histologic grad ing In all animals receiving medium or high doses of IL-1ra. Low doses of IL-1ra (1.0 mg/kg) had modest effects if given before, but no effe ct if given after, induction of pancreatitis. Conclusions. The proinfl ammatory cytokines IL-6 and TNF-alpha are elevated during experimental acute pancreatitis and correlate well with the severity of local panc reatic destruction. Blockade of the cytokine cascade at the level of t he IL-1 receptor before or soon after induction of pancreatitis signif icantly attenuates the rise in these cytokines and is associated with decreased severity of pancreatitis and reduced intrinsic pancreatic da mage.