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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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Rectal bleeding score over 7 d after water in WT or DSS oral treatment in WT, iNOS−/−, p47phox−/−, and SODTg mice (n = 9/group). a versus WT plus water; b versus WT plus DSS; c versus iNOS−/− plus DSS; d versus p47phox−/−; and e versus SODTg plus DSS. Mean ± SEM. P < 0.05.
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fig3: Rectal bleeding score over 7 d after water in WT or DSS oral treatment in WT, iNOS−/−, p47phox−/−, and SODTg mice (n = 9/group). a versus WT plus water; b versus WT plus DSS; c versus iNOS−/− plus DSS; d versus p47phox−/−; and e versus SODTg plus DSS. Mean ± SEM. P < 0.05.

Mentions: DSS treatment of WT mice for 7 d was associated with significant changes in body weight starting on day 5 (Fig. 1) and the appearance of fecal blood on day 4 (Fig. 2) . Only mild alterations were seen in stool consistency and no mortality was observed. Drinking volume was similar in all groups (data not shown). DAI scores in DSS-treated mice were lowest in the iNOS−/− mice compared with WT controls (significant from day 4 to day 7; Fig. 3) .


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)

Rectal bleeding score over 7 d after water in WT or DSS oral treatment in WT, iNOS−/−, p47phox−/−, and SODTg mice (n = 9/group). a versus WT plus water; b versus WT plus DSS; c versus iNOS−/− plus DSS; d versus p47phox−/−; and e versus SODTg plus DSS. Mean ± SEM. P < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Rectal bleeding score over 7 d after water in WT or DSS oral treatment in WT, iNOS−/−, p47phox−/−, and SODTg mice (n = 9/group). a versus WT plus water; b versus WT plus DSS; c versus iNOS−/− plus DSS; d versus p47phox−/−; and e versus SODTg plus DSS. Mean ± SEM. P < 0.05.
Mentions: DSS treatment of WT mice for 7 d was associated with significant changes in body weight starting on day 5 (Fig. 1) and the appearance of fecal blood on day 4 (Fig. 2) . Only mild alterations were seen in stool consistency and no mortality was observed. Drinking volume was similar in all groups (data not shown). DAI scores in DSS-treated mice were lowest in the iNOS−/− mice compared with WT controls (significant from day 4 to day 7; Fig. 3) .

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