Modulation of endogenous nitric oxide synthase in experimental acute pancreatitis: role of anti-ICAM-1 and oxygen free radical scavengers.

Abstract

OBJECTIVE:

To evaluate, in an experimental model of acute pancreatitis, the impact of nitric oxide on the disease process and the interaction between nitric oxide and oxygen free radicals.

SUMMARY BACKGROUND DATA:

Nitric oxide and oxygen free radicals are involved in the pathophysiology of acute pancreatitis. It is well established that oxygen free radicals play an important role in the development of pancreatic cell damage and remote organ failure, but the impact of nitric oxide on the disease process and the interactions between the two radical species remain controversial.

METHODS:

Necrotizing pancreatitis (NP) was induced in Wistar rats by intraductal sodium taurocholate infusion after pretreatment with isotonic saline (NP-S), superoxide dismutase/catalase (NP-SOD/CAT), or an anti-ICAM-1 antibody (aICAM-1). Sham-operated rats received isotonic saline (SHX). After an observation period of 5 minutes and 24 hours, the pancreas was removed for microscopy, glutathione, and myeloperoxidase (MPO) analysis. The inducible NO synthase (NOS-2) was detected by Western blotting or RT-PCR. Serum was analyzed for nitrite/nitrate (NO2-/NO3-) and S-nitrosothioles (RSNO), while plasma was used to assay for trypsinogen activation peptides (TAP).

RESULTS:

NP-S animals showed a significant decrease in GSH levels after NP-induction as compared with animals under therapy. Increased MPO levels in the NP-S group were significantly reduced by aICAM-1 while SOD/CAT injection showed no changes. Serum NO-derivatives peaked at 12 hours while TAP levels had a maximum at 6 hours after NP induction, and were lower after aICAM-1 application SOD/CAT treatment increased both parameters. Extended acinar cell damage and inflammatory infiltrate developed in NP-S animals and was significantly improved by SOD/CAT and aICAM-1 treatment. RT-PCR and Western-blot analysis revealed NOS-2 expression in the NP-S group, which was reduced by radical scavengers and aICAM-1.

CONCLUSION:

Enhanced nitric oxide synthase expression and increased nitric oxide derivatives are found during severe acute pancreatitis. Oxygen free radicals and neutrophils seem to be potent and important regulation mechanisms for nitric oxide synthase activity and nitric oxide-mediated toxicity but imply only a secondary role for nitric oxide in the local pathologic mechanism of this disease.

• Authors: B Rau, A Bauer, A Wang, F Gansauge, H Weidenbach, T Nevalainen, B Poch, H G Beger, A K Nussler
• Journal: Annals of surgery (Ann Surg) Vol. 233 Issue 2 Pg. 195-203 (Feb 2001) ISSN: 0003-4932 [Print] United States
• PMID: 11176125 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Free Radical Scavengers
• Nitric Oxide
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nos2 protein, rat

Topics

• Animals
• Blotting, Western
• Free Radical Scavengers
• Male
• Nitric Oxide (physiology)
• Nitric Oxide Synthase (metabolism)
• Nitric Oxide Synthase Type II
• Oxidative Stress (physiology)
• Pancreatitis, Acute Necrotizing (physiopathology)
• Rats
• Rats, Wistar