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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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Clinical score (DAI) during 7 d of DSS administration in WT and p47phox−/− mice that received concomitant 1400W (or saline in controls) using a subcutaneously implanted miniosmotic pump (n = 5/group). a versus WT saline plus DSS, b versus p47phox−/− 1400W plus DSS, c versus p47phox−/− saline plus DSS. Mean ± SEM. P < 0.05.
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fig5: Clinical score (DAI) during 7 d of DSS administration in WT and p47phox−/− mice that received concomitant 1400W (or saline in controls) using a subcutaneously implanted miniosmotic pump (n = 5/group). a versus WT saline plus DSS, b versus p47phox−/− 1400W plus DSS, c versus p47phox−/− saline plus DSS. Mean ± SEM. P < 0.05.

Mentions: When compared with saline-treated controls the 1400W-treated WT mice lost significantly less weight (11.6 ± 1.8% versus 6.1 ± 0.9%, respectively), and exhibited minimal rectal bleeding that was detectable only by testing for fecal occult blood, whereas all controls exhibited gross rectal bleeding. Daily measurements of the DAI demonstrated the delayed and attenuated clinical course of colitis after blockade of iNOS by 1400W (Fig. 5) , which resulted in less tissue damage as summarized in Table III.


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)

Clinical score (DAI) during 7 d of DSS administration in WT and p47phox−/− mice that received concomitant 1400W (or saline in controls) using a subcutaneously implanted miniosmotic pump (n = 5/group). a versus WT saline plus DSS, b versus p47phox−/− 1400W plus DSS, c versus p47phox−/− saline plus DSS. Mean ± SEM. P < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Clinical score (DAI) during 7 d of DSS administration in WT and p47phox−/− mice that received concomitant 1400W (or saline in controls) using a subcutaneously implanted miniosmotic pump (n = 5/group). a versus WT saline plus DSS, b versus p47phox−/− 1400W plus DSS, c versus p47phox−/− saline plus DSS. Mean ± SEM. P < 0.05.
Mentions: When compared with saline-treated controls the 1400W-treated WT mice lost significantly less weight (11.6 ± 1.8% versus 6.1 ± 0.9%, respectively), and exhibited minimal rectal bleeding that was detectable only by testing for fecal occult blood, whereas all controls exhibited gross rectal bleeding. Daily measurements of the DAI demonstrated the delayed and attenuated clinical course of colitis after blockade of iNOS by 1400W (Fig. 5) , which resulted in less tissue damage as summarized in Table III.

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