Susceptibility to Cerulein-Induced Pancreatitis in Inducible Nitric Oxide Synthase-Deficient Mice

Abstract

Production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been proposed as a pathogenic factor in acute pancreatitis, but its role has still not been fully examined. The present study explored the role of iNOS in cerulein-induced acute pancreatitis using iNOS-deficient mice. Twelve- to 14-week-old male mice (C57B1/6 and iNOS-deficient) were administered cerulein by intraperitoneal (i.p.) injection at hourly intervals for 7 hours and killed 24 hours later after the first dose. Pancreatic wet weight, pancreatic myeloperoxidase (MPO) activity, and levels of plasma nitrite and serum amylase were measured. In another experiment isosorbide dinitrate (an NO donor) was given by oral gavage every 6 hours for 24 hours beginning simultaneously with cerulein injections in iNOS-deficient mice. Cerulein administration dose-dependently increased pancreatic wet weight, myeloperoxidase activity, and levels of nitrite and amylase in C57B1/6 mice. These parameters (except nitrite levels) were significantly intensified in iNOS-deficient mice. At the dose employed, cerulein failed to increase nitrite levels in iNOS-deficient mice. The susceptibility to cerulein toxicity in iNOS-deficient mice was abolished by NO donor treatment. NO release from an iNOS source appears to play a protective role in cerulein-induced pancreatitis. At least in part, NO may prevent neutrophil accumulation after cerulein administration.

Pathogenic Role of Endothelial Nitric Oxide Synthase (eNOS/NOS-III) in Cerulein-Induced Rat Acute Pancreatitis

“…Cuzzocrea et al [21] reported that iNOS-deficient mice showed resistance to acute pancreatitis induced by cerulein, suggesting a deleterious role of iNOS/NO in the pathogenesis. By contrast, Qui et al [22] reported that iNOS-deficient mice were more susceptible to cerulein-induced pancreatitis. Furthermore, using eNOS-deficient mice, DiMagno et al [8] showed a protective influence of eNOS/NO on ceruleininduced acute pancreatitis.…”

Expression of Nitric Oxide Synthase Isoforms and Nitric Oxide Production in Acute Pancreatitis and Associated Lung Injury

“…Studies have shown that iNOS response varies between pancreatitis models and reported that, in necrotizing pancreatitis, various soluble factors activate the macrophage/monocyte system and cause increased NO production by iNOS [23] . Two groups reported on the conflicting effects of iNOS gene deletion on the late inflammatory phase of cerulein-induced AP in mice; iNOS gene deletion was protective in one study [13] and injurious in the other [24] . Our study shows that iNOS expression is substantially upregulated in the pancreas and acinar cells in response to supramaximal cerulein.…”

The Role of Nitric Oxide in Experimental Cerulein Induced Pancreatitis

“…These differing results could result from different models of pancreatitis, or may be attributable to different drug regimens that achieve partial or complete inhibition of NOS. Recently, special iNOS gene deletion "knockout" mice have been used to characterize the impact of NO form iNOS during acute pancreatitis (8,28). However, these animal studies also have yielded ambiguous evidence in support of the role of NO in pancreatitis.…”