Differential effects of caspase-1/interleukin-1 beta-converting enzyme on acinar cell necrosis and apoptosis in severe acute experimental pancreatitis

There is recent experimental evidence that inhibition of caspase-1/interleu kin-1 beta converting enzyme (ICE) significantly ameliorates overall severi ty 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 s tudy. Severe acute pancreatitis (SAP) was induced by retrograde infusion of 4% sodium taurocholate in rats treated with isotonic saline or a highly se lective, irreversible inhibitor of ICE. After 3, 6, and 24 hours, 3 and 7 d ays, acinar cell death by necrosis and apoptosis, as well as intrapancreati c and systemic interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alp ha (TNF-alpha) expression, was assessed. Treatment with the ICE inhibitor s ignificantly reduced the extent of acinar cell necrosis accounting for majo r parenchymal destruction. In contrast, apoptosis was confined to the posta cute course of the disease and was closely related to tubular complex forma tion, both remaining unchanged. Whereas intrapancreatic IL-1 beta mRNA expr ession was highly up-regulated in both treated and untreated animals, activ e IL-1 beta protein expression and subsequent neutrophil tissue infiltratio n was dramatically decreased in the ICE-inhibited group. Parallel to the on set of enhanced apoptotic acinar cell death and tubular complex formation. TNF-alpha mRNA and protein expression was up-regulated, with levels being l ower 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 necro sis in SAP. Herein, IL-1 beta -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 m echanism, but may be influenced by TNF-alpha.