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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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NOX levels in serum of different mutant and WT mice that received DSS in drinking water over 7 d or millipore water (H2O) in controls (n = 5/DSS-treated group; n = 3/H2O-treated group). Serum concentrations were measured using a modification of the standard Griess assay and absorbances were read at 540 nm in a spectrophotometer. Results are expressed as μM NOX. Mean ± SEM. *P < 0.05 vs. H2O-treated WT. #P < 0.05 vs. DSS-treated WT. ‡P < 0.05 vs. saline-pump.
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fig7: NOX levels in serum of different mutant and WT mice that received DSS in drinking water over 7 d or millipore water (H2O) in controls (n = 5/DSS-treated group; n = 3/H2O-treated group). Serum concentrations were measured using a modification of the standard Griess assay and absorbances were read at 540 nm in a spectrophotometer. Results are expressed as μM NOX. Mean ± SEM. *P < 0.05 vs. H2O-treated WT. #P < 0.05 vs. DSS-treated WT. ‡P < 0.05 vs. saline-pump.

Mentions: DSS administration in drinking water over 7 d resulted in a 250% increase of serum NOX in WT mice when compared with controls given millipore water. Serum levels of NOX after DSS were significantly lowered by either genetic deletion of iNOS (−75.1%) or blockade of iNOS using 1400W (up to −57.8%). Interestingly, serum NOX in DSS-treated SODTg was 33% higher compared with DSS-treated WT, however this change did not achieve statistical significance. No differences were found between WT and p47phox−/− mice after saline pump implantation and DSS administration. As expected, the lowest serum NOX levels were detected in DSS-treated iNOS−/− (Fig. 7) .


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)

NOX levels in serum of different mutant and WT mice that received DSS in drinking water over 7 d or millipore water (H2O) in controls (n = 5/DSS-treated group; n = 3/H2O-treated group). Serum concentrations were measured using a modification of the standard Griess assay and absorbances were read at 540 nm in a spectrophotometer. Results are expressed as μM NOX. Mean ± SEM. *P < 0.05 vs. H2O-treated WT. #P < 0.05 vs. DSS-treated WT. ‡P < 0.05 vs. saline-pump.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2195977&req=5

fig7: NOX levels in serum of different mutant and WT mice that received DSS in drinking water over 7 d or millipore water (H2O) in controls (n = 5/DSS-treated group; n = 3/H2O-treated group). Serum concentrations were measured using a modification of the standard Griess assay and absorbances were read at 540 nm in a spectrophotometer. Results are expressed as μM NOX. Mean ± SEM. *P < 0.05 vs. H2O-treated WT. #P < 0.05 vs. DSS-treated WT. ‡P < 0.05 vs. saline-pump.
Mentions: DSS administration in drinking water over 7 d resulted in a 250% increase of serum NOX in WT mice when compared with controls given millipore water. Serum levels of NOX after DSS were significantly lowered by either genetic deletion of iNOS (−75.1%) or blockade of iNOS using 1400W (up to −57.8%). Interestingly, serum NOX in DSS-treated SODTg was 33% higher compared with DSS-treated WT, however this change did not achieve statistical significance. No differences were found between WT and p47phox−/− mice after saline pump implantation and DSS administration. As expected, the lowest serum NOX levels were detected in DSS-treated iNOS−/− (Fig. 7) .

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