Differential Effects of Caspase-1/Interleukin-1β–Converting Enzyme on Acinar Cell Necrosis and Apoptosis in Severe Acute Experimental Pancreatitis

Abstract

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.

Cigarette smoke-induced pancreatic damage—experimental data

“…Macrophage inflammatory protein 1 alpha, a protein involved in chemotraction of macrophages, was induced in animals with morphologic pancreatic lesions, while expression was low or not detectable in the pancreata of animals treated with two cigarettes twice a day not showing altered histology [23]. Similar expression profiles were detected for interleukin 1 beta, a molecule expressed by acinar cells and immune cells which is involved in the first line of immune response [24] and transforming growth fact beta 1 indicating the involvement of TGF beta in reorganization of the pancreatic acinar tissue [25]. These data indicated that the inhalation of cigarette smoke induces an ongoing pancreatic inflammatory process related to transforming growth fact beta leading to acinar cell destruction with reorganization of circumscribed areas of the exocrine pancreas to connective tissue.…”

IL-1β-converting enzyme (caspase-1) in intestinal inflammation

“…In other models of in vivo inflammation, the role of ICE has been characterized in more detail. For instance, beneficial effects of ICE blockade or ICE deficiency have been demonstrated in toxin-induced pancreatitis (32,33) and collagen-induced arthritis (34).…”

Effect of Baicalin on Inflammatory Mediator Levels and Microcirculation Disturbance in Rats With Severe Acute Pancreatitis

“…Some experiments have proved that the contents of IL-1β are positively correlated with the mortality rates of rats [18]. Paszkowski et al [19,20] have found that IL-1β mRNA is expressed in normal lung tissues. In SAP, the expression of IL-1β mRNA is significantly enhanced, and the expression levels of IL-1β mRNA are parallel to the severity of SAP.…”