SUMMARY:There is recent experimental evidence that inhibition of caspase-1/interleukin-1 converting enzyme (ICE) significantly ameliorates overall severity and survival in severe acute experimental pancreatitis. However, little is known about the effects of this approach on the dynamics and mechanisms of local acinar cell damage, which we aimed to investigate in the present study. Severe acute pancreatitis (SAP) was induced by retrograde infusion of 4% sodium taurocholate in rats treated with isotonic saline or a highly selective, irreversible inhibitor of ICE. After 3, 6, and 24 hours, 3 and 7 days, acinar cell death by necrosis and apoptosis, as well as intrapancreatic and systemic interleukin-1 (IL-1) and tumor necrosis factor-␣ (TNF-␣) expression, was assessed. Treatment with the ICE inhibitor significantly reduced the extent of acinar cell necrosis accounting for major parenchymal destruction. In contrast, apoptosis was confined to the postacute course of the disease and was closely related to tubular complex formation, both remaining unchanged. Whereas intrapancreatic IL-1 mRNA expression was highly up-regulated in both treated and untreated animals, active IL-1 protein expression and subsequent neutrophil tissue infiltration was dramatically decreased in the ICE-inhibited group. Parallel to the onset of enhanced apoptotic acinar cell death and tubular complex formation, TNF-␣ mRNA and protein expression was up-regulated, with levels being lower in ICE inhibitor-treated rats. We conclude that activation of caspase-1/ICE plays a central role in the progression of acinar cell death by necrosis in SAP. Herein, IL-1-mediated neutrophil infiltration seems to be a crucial step in enhanced cellular destruction. In contrast, acinar cell apoptosis contributes to ductal transformation and is independent of this mechanism, but may be influenced by TNF-␣ (Lab Invest 2001, 81:1001-1013.