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Original Article

Christian F. Krieglstein^1,2, Wolfgang H. Cerwinka¹, F. Stephen Laroux¹, James W. Salter¹, Janice M. Russell¹, Guido Schuermann², Matthew B. Grisham¹, Christopher R. Ross³ and D. Neil Granger¹

¹ Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130
² Department of General Surgery, Westfalian Wilhelm's-University, D-48149 Münster, Germany
³ Department of Anatomy and Physiology, Kansas State University, College of Veterinary Medicine, Manhattan, KA 66506

Address correspondence to D. Neil Granger, Department of Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932. Phone: 318-675-6011; Fax: 318-675-6005; E-mail: dgrang{at}lsuhsc.edu

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.

Key Words: inflammatory bowel diseases • nitric oxide synthase • superoxide dismutase • NADPH oxidase • dextran sulfate sodium

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