Intrapancreatic activation of trypsinogen is believed to play a critical role in the initiation of acute pancreatitis, but mechanisms responsible for intrapancreatic trypsinogen activation during pancreatitis have not been clearly defined. In previous in vitro studies, we have shown that intra-acinar cell activation of trypsinogen and acinar cell injury in response to supramaximal secretagogue stimulation could be prevented by the cell permeant cathepsin B inhibitor E64d (Saluja A, Donovan EA, Yamanaka K, Yamaguchi Y, Hofbauer B, and Steer ML. Gastroenterology 113: 304-310, 1997). The present studies evaluated the role of intrapancreatic trypsinogen activation, this time under in vivo conditions, in two models of pancreatitis by using another highly soluble cell permeant cathepsin B inhibitor, L-3-trans-(propylcarbamoyl)oxirane-2-carbonyl-L-isoleucyl-L-proline methyl ester (CA-074me). Intravenous administration of CA-074me (10 mg/kg) before induction of either secretagogue-elicited pancreatitis in mice or duct infusion-elicited pancreatitis in rats markedly reduced the extent of intrapancreatic trypsinogen activation and substantially reduced the severity of both pancreatitis models. These observations support the hypothesis that, during the early stages of pancreatitis, trypsinogen activation in the pancreas is mediated by the lysosomal enzyme cathepsin B. Our findings also suggest that pharmacological interventions that inhibit cathepsin B may prove useful in preventing acute pancreatitis or reducing its severity.
Inhibition of cyclooxygenase-2 ameliorates the severity of pancreatitis and associated lung injury. Am J Physiol Gastrointest Liver Physiol 283: G1166-G1174, 2002. First published July 17, 2002 10.1152/ajpgi.00370.2001.-Cyclooxygenase-2 (COX-2), a widely distributed enzyme, plays an important role in inflammation. We have studied the role of COX-2 in acute pancreatitis and pancreatitis-associated lung injury using both the pharmacological inhibition of COX-2 and genetic deletion of COX-2. Pancreatitis was induced in mice by 12 hourly injections of cerulein. The severity of pancreatitis was assessed by measuring serum amylase, pancreatic trypsin activity, intrapancreatic sequestration of neutrophils, and acinar cell necrosis. The severity of lung injury was evaluated by measuring lactate dehydrogenase levels in the bronchoalveolar lavage fluid and by quantitating neutrophil sequestration in the lung. In both the pharmacologically inhibited and genetically altered mice, the severity of pancreatitis and pancreatitis-associated lung injury was reduced compared with the noninhibited strains of COX-2-sufficient mice. This reduction in injury indicates that COX-2 plays an important proinflammatory role in pancreatitis and its associated lung injury. Our findings support the concept that COX-2 inhibitors may play a beneficial role in the prevention of acute pancreatitis or in the reduction of its severity.prostaglandin; proinflammatory; cerulein; neutrophil; heat shock protein 70; inducible nitric oxide synthase; trypsin; myeloperoxidase CLINICAL ACUTE PANCREATITIS can present with varying degrees of severity. It is frequently associated with lung injury, manifesting as the adult respiratory distress syndrome. Approximately 80% of patients experience a mild attack with minimal sequelae; however, the other 20% of patients develop severe disease with a mortality rate that can reach 40% (37). The factors that determine the development and ultimate severity of pancreatitis are still not fully understood.The initiation of prostanoid synthesis from arachidonic acid involves the enzyme cyclooxygenase (COX), an enzyme that is also referred to as PGH synthase or PG endoperoxide synthase, because it is also the ratelimiting enzyme for PGE 2 synthesis. Two COX isoforms have been identified: a constitutive form (COX-1), which is thought to have an important housekeeping function, and an inducible form (COX-2), which has been implicated as an important proinflammatory mediator (21). COX-2 is upregulated in response to a variety of proinflammatory stimuli including IL-1, TNF-␣, and bacterial lipopolysaccharide (1, 9, 23). COX-2 mRNA and protein levels are increased during experimental pancreatitis, but the role of COX-2 in pancreatitis has not been well defined (13).In this communication, we report the result of studies dealing with the role of COX-2 in acute pancreatitis and pancreatitis-associated lung injury. In our studies, some mice were pretreated with COX-2 inhibitors (15, 33), whereas other mice were bred with genetic deleti...
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