Therapeutic application of caspase 1/interleukin-1beta-converting enzyme inhibitor decreases the death rate in severe acute experimental pancreatitis.
OBJECTIVE
To assess the effect of therapeutic inhibition of interleukin 1beta-converting enzyme (ICE) in an experimental model of severe acute pancreatitis (SAP).


BACKGROUND
Several lines of evidence suggest that cytokines activated by ICE play an instrumental role in the course of acute pancreatitis. Recent studies have shown that pharmacologic or genetic blockade of ICE significantly ameliorates the overall severity of and the death rate in SAP.


METHODS
Severe acute pancreatitis was induced by infusion of 5% sodium taurocholate in Wistar rats. A new, highly selective, irreversible inhibitor of ICE was intraperitoneally applied at a dosage of 0.25 mg every 12 hours. Control animals in group 1 received treatment with saline; in group 2 rats, ICE inhibition was started 6 hours after the onset of pancreatitis; and in group 3 rats, ICE inhibition was started 12 hours after the onset of pancreatitis. After a 7-day observation period, surviving rats were killed and blood, plasma, pancreas, lung, and liver were used for subsequent analysis.


RESULTS
Inhibition of ICE decreased the 7-day death rate from 87.5% to 38.9% irrespective whether treatment was started 6 hours or 12 hours after induction of SAP. Morphometric analysis revealed a significant reduction of acinar cell necrosis in both treated groups, whereas pancreatitis-associated pulmonary and hepatic damage was uniformly low and not influenced by ICE inhibition. Tissue myeloperoxidase concentrations were dramatically decreased in the pancreas and the lung after either regimen of ICE inhibitor treatment. In contrast to lung and liver, marked upregulation of interleukin 1beta, tumor necrosis factor alpha, and ICE mRNA was observed in the pancreas, with levels of interleukin 1beta and tumor necrosis factor alpha being reduced in ICE-inhibited animals. Compared with nontreated rats, plasma amylase levels were higher in both treatment groups, whereas lipase and hematocrit showed no difference. Changes of the differential white blood count including neutrophils, lymphocytes, and monocytes were attenuated in both groups after ICE inhibitor treatment.


CONCLUSIONS
Pharmacologic inhibition of ICE significantly improves the overall severity of and the death rate in SAP. A substantial reduction of neutrophil-mediated tissue injury in pancreas and lung seems to contribute to the beneficial effects of this approach. Moreover, ICE inhibition is still effective after a therapeutic window of 12 hours. Based on the current findings, future studies on the clinical application of ICE-inhibiting substances in acute pancreatitis seem to be promising.
Paszkowski
Adam S
AS
Departments of General Surgery and Pathology, University of Ulm, Ulm, Germany.
Rau
Bettina
B
Mayer
Jens M
JM
Möller
Peter
P
Beger
Hans G
HG
D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D020170:Caspase 1 / Q000235:genetics; D061945:Caspase Inhibitors; D003627:Data Interpretation, Statistical; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006400:Hematocrit; D007375:Interleukin-1 / Q000235:genetics; D008049:Lipase / Q000097:blood; D008297:Male; D009336:Necrosis; D010179:Pancreas / Q000473:pathology; D010195:Pancreatitis / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D008049:Lipase; D000681:Amylases; D020170:Caspase 1