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Regulation of murine intestinal inflammation by reactive metabolites of oxygen and nitrogen: divergent roles of superoxide and nitric oxide.

Krieglstein CF, Cerwinka WH, Laroux FS, Salter JW, Russell JM, Schuermann G, Grisham MB, Ross CR, Granger DN - J. Exp. Med. (2001)

Bottom Line: We have investigated the role of three key RONS-metabolizing enzymes (inducible nitric oxide synthase [iNOS], superoxide dismutase [SOD], nicotinamide adenine dinucleotide phosphate [NADPH] oxidase) in a murine model of IBD.WT mice responded to DSS feeding with progressive weight loss, bloody stools, elevated serum NO(X) and colonic mucosal injury with neutrophil infiltration.These findings reveal divergent roles for superoxide and iNOS-derived NO in intestinal inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.

ABSTRACT
Several reports have implicated reactive oxygen and nitrogen metabolites (RONS) in the initiation and/or progression of inflammatory bowel diseases (IBDs). We have investigated the role of three key RONS-metabolizing enzymes (inducible nitric oxide synthase [iNOS], superoxide dismutase [SOD], nicotinamide adenine dinucleotide phosphate [NADPH] oxidase) in a murine model of IBD. Mice genetically deficient ((-/-)) in either iNOS or the p47phox subunit of NADPH oxidase, transgenic (Tg) mice that overexpress SOD, and their respective wild-type (WT) littermates were fed dextran sulfate sodium (DSS) in drinking water for 7 days to induce colitis. In addition, the specific iNOS inhibitor 1400W was used in DSS-treated WT and p47phox(-/-) mice. WT mice responded to DSS feeding with progressive weight loss, bloody stools, elevated serum NO(X) and colonic mucosal injury with neutrophil infiltration. Both the onset and severity of colitis were significantly attenuated in iNOS(-/-) and 1400W-treated WT mice. While the responses to DSS did not differ between WT and p47phox(-/-) mice, enhanced protection was noted in 1400W-treated p47phox(-/-) mice. Interestingly, SOD(Tg) mice exhibited more severe colitis than their WT littermates. These findings reveal divergent roles for superoxide and iNOS-derived NO in intestinal inflammation.

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MPO in colonic tissue of water-treated WT mice or after 7 d of treatment with DSS in WT, iNOS−/−, p47phox−/−, and SODTg mice that were housed under SPF conditions (n = 9/group) or WT and iNOS mice housed under conventional condition (n = 5/group). Tissue concentrations were measured by the O-dianisidine method. The change in absorbance was read at 460 nm in a spectrophotometer. MPO activity was expressed as the amount of enzyme necessary to produce a change in absorbance of 1.0 per min per gram of wet weight of tissue. Mean ± SEM. *P < 0.05 vs. water-treated WT. #P < 0.05 vs. DSS-treated WT.
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fig4: MPO in colonic tissue of water-treated WT mice or after 7 d of treatment with DSS in WT, iNOS−/−, p47phox−/−, and SODTg mice that were housed under SPF conditions (n = 9/group) or WT and iNOS mice housed under conventional condition (n = 5/group). Tissue concentrations were measured by the O-dianisidine method. The change in absorbance was read at 460 nm in a spectrophotometer. MPO activity was expressed as the amount of enzyme necessary to produce a change in absorbance of 1.0 per min per gram of wet weight of tissue. Mean ± SEM. *P < 0.05 vs. water-treated WT. #P < 0.05 vs. DSS-treated WT.

Mentions: DSS administration was followed by a significant increase in MPO activity in all mice (Fig. 4) . MPO activity corresponded closely with the clinical and histological grading of inflammation in the different groups (Figs. 1–3 and Table I). Whereas WT and p47phox−/− mice showed approximately equivalent increases in MPO activity (14-fold and 13-fold, respectively), the increment in colonic MPO was significantly less pronounced (7.4-fold) in iNOS−/− mice, but more pronounced in SODTg mice (23-fold) after DSS administration (Fig. 4).


Regulation of murine intestinal inflammation by reactive metabolites of oxygen and nitrogen: divergent roles of superoxide and nitric oxide.

Krieglstein CF, Cerwinka WH, Laroux FS, Salter JW, Russell JM, Schuermann G, Grisham MB, Ross CR, Granger DN - J. Exp. Med. (2001)

MPO in colonic tissue of water-treated WT mice or after 7 d of treatment with DSS in WT, iNOS−/−, p47phox−/−, and SODTg mice that were housed under SPF conditions (n = 9/group) or WT and iNOS mice housed under conventional condition (n = 5/group). Tissue concentrations were measured by the O-dianisidine method. The change in absorbance was read at 460 nm in a spectrophotometer. MPO activity was expressed as the amount of enzyme necessary to produce a change in absorbance of 1.0 per min per gram of wet weight of tissue. Mean ± SEM. *P < 0.05 vs. water-treated WT. #P < 0.05 vs. DSS-treated WT.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195977&req=5

fig4: MPO in colonic tissue of water-treated WT mice or after 7 d of treatment with DSS in WT, iNOS−/−, p47phox−/−, and SODTg mice that were housed under SPF conditions (n = 9/group) or WT and iNOS mice housed under conventional condition (n = 5/group). Tissue concentrations were measured by the O-dianisidine method. The change in absorbance was read at 460 nm in a spectrophotometer. MPO activity was expressed as the amount of enzyme necessary to produce a change in absorbance of 1.0 per min per gram of wet weight of tissue. Mean ± SEM. *P < 0.05 vs. water-treated WT. #P < 0.05 vs. DSS-treated WT.
Mentions: DSS administration was followed by a significant increase in MPO activity in all mice (Fig. 4) . MPO activity corresponded closely with the clinical and histological grading of inflammation in the different groups (Figs. 1–3 and Table I). Whereas WT and p47phox−/− mice showed approximately equivalent increases in MPO activity (14-fold and 13-fold, respectively), the increment in colonic MPO was significantly less pronounced (7.4-fold) in iNOS−/− mice, but more pronounced in SODTg mice (23-fold) after DSS administration (Fig. 4).

Bottom Line: We have investigated the role of three key RONS-metabolizing enzymes (inducible nitric oxide synthase [iNOS], superoxide dismutase [SOD], nicotinamide adenine dinucleotide phosphate [NADPH] oxidase) in a murine model of IBD.WT mice responded to DSS feeding with progressive weight loss, bloody stools, elevated serum NO(X) and colonic mucosal injury with neutrophil infiltration.These findings reveal divergent roles for superoxide and iNOS-derived NO in intestinal inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.

ABSTRACT
Several reports have implicated reactive oxygen and nitrogen metabolites (RONS) in the initiation and/or progression of inflammatory bowel diseases (IBDs). We have investigated the role of three key RONS-metabolizing enzymes (inducible nitric oxide synthase [iNOS], superoxide dismutase [SOD], nicotinamide adenine dinucleotide phosphate [NADPH] oxidase) in a murine model of IBD. Mice genetically deficient ((-/-)) in either iNOS or the p47phox subunit of NADPH oxidase, transgenic (Tg) mice that overexpress SOD, and their respective wild-type (WT) littermates were fed dextran sulfate sodium (DSS) in drinking water for 7 days to induce colitis. In addition, the specific iNOS inhibitor 1400W was used in DSS-treated WT and p47phox(-/-) mice. WT mice responded to DSS feeding with progressive weight loss, bloody stools, elevated serum NO(X) and colonic mucosal injury with neutrophil infiltration. Both the onset and severity of colitis were significantly attenuated in iNOS(-/-) and 1400W-treated WT mice. While the responses to DSS did not differ between WT and p47phox(-/-) mice, enhanced protection was noted in 1400W-treated p47phox(-/-) mice. Interestingly, SOD(Tg) mice exhibited more severe colitis than their WT littermates. These findings reveal divergent roles for superoxide and iNOS-derived NO in intestinal inflammation.

Show MeSH
Related in: MedlinePlus