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Reduced sensitivity of inducible nitric oxide synthase-deficient mice to chronic colitis
R Hokari1, S Kato, K Matsuzaki
1Second Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
Background:
Overproduction of nitric oxide by the inducible form of nitric oxide synthase (iNOS) has been implicated in colitis. Different authors have postulated both toxic and protective effects of nitric oxide (NO) in the pathophysiology of active inflammation. The objective of this study was to examine the role of iNOS in experimental chronic colitis using iNOS-deficient mice.
Methods:
For induction of colitis, mice received three cycles of 2% of dextran sodium sulfate (DSS) (M.W. 40,000) treatment in drinking water. The degree of colonic inflammation, leukocyte infiltration, and the expression of cell adhesion molecules were determined. INOS expression and nitrotyrosine were also determined by immunohistochemistry.
Results:
After DSS treatment, a moderate colitis with marked cell infiltration was observed. Intense expression of iNOS was observed on infiltrating cells as well as on the colonic mucosal epithelium in these animals. In the iNOS-deficient mice, tissue damage was significantly diminished. No iNOS or nitrotyrosine staining was found in iNOS-deficient mice. The number of infiltrating cells and the expression of mucosal adressin cell adhesion molecule-1 were significantly attenuated in the DSS-treated colon of iNOS-deficient mice.
Conclusion:
Induction of iNOS seems to act as a critical toxic effector molecule in the pathogenesis of chronic colonic inflammation.
Insights
Inducible nitric oxide synthase (iNOS) contributes to chronic colitis by causing tissue damage. Mice lacking iNOS showed significantly reduced inflammation and cell infiltration in experimental colitis, highlighting iNOS
Area of Science:
- Gastroenterology and Immunology
- Inflammatory Bowel Disease Research
Background:
- The role of nitric oxide (NO) in colitis pathogenesis is debated, with potential toxic and protective effects attributed to its overproduction by inducible nitric oxide synthase (iNOS).
- Understanding iNOS' specific contribution is crucial for developing targeted therapies for chronic inflammatory conditions of the colon.
Purpose of the Study:
- To investigate the role of iNOS in the development of experimental chronic colitis.
- To assess the impact of iNOS deficiency on colonic inflammation, leukocyte infiltration, and cell adhesion molecule expression.
Main Methods:
- Experimental chronic colitis was induced in mice using multiple cycles of dextran sodium sulfate (DSS) administration.
- iNOS-deficient mice and wild-type controls were used to compare disease severity.
- Colonic inflammation, leukocyte infiltration, iNOS expression, nitrotyrosine levels, and cell adhesion molecule expression were evaluated using histological and immunohistochemical analyses.
Main Results:
- DSS treatment induced moderate colitis with significant leukocyte infiltration and iNOS expression in wild-type mice.
- iNOS-deficient mice exhibited significantly diminished tissue damage, reduced leukocyte infiltration, and lower expression of mucosal adressin cell adhesion molecule-1.
- No iNOS or nitrotyrosine staining was detected in iNOS-deficient mice, confirming the absence of iNOS activity.
Conclusions:
- The induction of iNOS plays a critical role as a toxic effector molecule in the pathogenesis of chronic colonic inflammation.
- Targeting iNOS may represent a viable therapeutic strategy for managing chronic colitis.