Inhibition of cyclooxygenase-2 ameliorates the severity of pancreatitis and associated lung injury

Abstract

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...

Development of a new mouse model of acute pancreatitis induced by administration of l-arginine

“…Hematoxylin and eosin-stained sections of pancreas and lungs were evaluated microscopically by a person unaware of the treatment. The extent of injury was calculated by morphometry as described earlier (22). Pancreatic sections were stained for collagen with Sirius red as described by Junqueira et al (10).…”

Study progress on mechanism of severe acute pancreatitis complicated with hepatic injury

“…Many studies show that injury of the over activated neutrocyte on self tissue is an important cause of systemic complications due to AP (Chen et al, 2001;de Dios et al, 2002;Descamps et al, 2003;Ammori, 2003;Shields et al, 2001;Demols and Deviere, 2003;Zhao et al, 2003;Zhou et al, 2002;Song et al, 2002;Brady et al, 2002;Clemons et al, 2002;Hartwig et al, 2002c;Mikami et al, 2002). The neutrophilic granulocyte stimulated by pancreatitis can release inflammatory cytokines such as TNF-α (Cassatella, 1995;Ni et al, 1998;Ogawa, 1998).…”

Ischemic preconditioning inhibits development of edematous cerulein-induced pancreatitis: Involvement of cyclooxygenases and heat shock protein 70

“…Previous experimental studies on mice [13,14] have shown that pharmacological inhibition of COX-2 or COX-2 gene disruption ameliorates the severity of pancreatitis and the pancreatitis-associated lung injury. In contrast, in the rat model of pancreatitis, Foitzik et al [32] , have found some beneficial systemic effects of COX-2 inhibition on acute pancreatitis, such as an improvement of renal and respiratory function, but they have not observed any significant effect of COX-2 inhibition on histological score of pancreatic damage or plasma level of trypsinogen activation peptides.…”

“…The role of COX-2 in pancreatic pathology is unclear. Studies performed by Song et al [13] , and Ethridge et al [14] , with mice have shown that pharmacological inhibition of COX-2 or COX-2 gene disruption reduces the severity of pancreatitis and pancreatitis-associated lung injury. On the other hand, our own study has shown that inhibition of COX-2 abolishes the protective effect of hepatocyte growth factor (HGF) against cerulein-induced pancreatitis [15] .…”