| Cyclooxygenase (COX) catalyzes the rate-limiting step in prostaglandin production; the inducible isoform, COX-2, has been implicated in a variety of inflammatory processes and its expression is controlled, in part, by the transcription factor, NF-kappaB. The role of COX in acute pancreatitis and pancreatitis-associated lung injury is not known. We hypothesize that COX-2 is a central modulator in acute pancreatitis. Methods. Acute pancreatitis was induced in Swiss Webster mice or mice deficient in the COX-2 (Ptgs2) or the COX-1 (Ptgs1) genes. Pancreata and lungs were harvested; histologic sections of these tissues were scored. COX-2, COX-1, and PPARgamma expression, NF-kappaB activity, myeloperoxidase (MPO) activity (a measurement of neutrophil sequestration) and, serum amylase levels were determined. Results. Acute pancreatitis was associated with induction of COX-2, HSP70, and PPARgamma expression. NF-kappaB DNA-binding activity is also markedly increased following pancreatitis. Treatment with COX-2 inhibitors significantly decreased the severity of pancreatitis. Furthermore, Ptgs2 deficient mice demonstrated minimal histologic evidence of pancreatitis, a marked attenuation in the severity of lung injury and a significant reduction in MPO activity. Moreover, the expression of COX-2, and therefore the severity of pancreatitis, was effected by the selective NF-kappaB inhibitor, NBD peptide, and the PPARgamma agonist 15-dPGJ2. Additionally, the expression of COX-2 appears to be necessary for the activity of HSF-1 and the expression of HSP70. Conclusions. Inhibition of COX-2 by either pharmacologic inhibition or selective genetic deletion markedly attenuated the severity of acute pancreatitis. By affecting the activity of upstream modulators of COX-2, we decreased the expression of COX-2 and, therefore, decreased the severity of acute pancreatitis. We also show that COX-2 expression is necessary for the expression of cellular survival proteins. Taken together, we show that COX-2 is crucial in modulating the severity of pancreatitis and appears to inhibit the recovery of the tissue following cellular damage. |
