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Paradoxical roles of different nitric oxide synthase isoforms in colonic injury

¹Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, T2N 4N1 Canada; ²Gastrointestinal Unit, Center for Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston 02114; and ³Veterans Affairs Boston Healthcare, Boston, Massachusetts 02131

Submitted 18 July 2003 ; accepted in final form 20 August 2003

Nitric oxide (NO) is a free radical that is largely produced by three isoforms of NO synthase (NOS): neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). NO regulates numerous processes in the gastrointestinal tract; however, the overall role that NO plays in intestinal inflammation is unclear. NO is upregulated in both ulcerative colitis and Crohn's disease as well as in animal models of colitis. There have been conflicting reports on whether NO protects or exacerbates injury in colitis or is simply a marker of inflammation. To determine whether the site, timing, and level of NO production modulate the effect on the inflammatory responses, the dextran sodium sulfate model of colitis was assessed in murine lines rendered deficient in iNOS, nNOS, eNOS, or e/nNOS by targeted gene disruption. The loss of nNOS resulted in more severe disease and increased mortality, whereas the loss of eNOS or iNOS was protective. Furthermore, concomitant loss of eNOS reversed the susceptibility found in nNOS-/- mice. Deficiencies in specific NOS isoforms led to distinctive alterations of inflammatory responses, including changes in leukocyte recruitment and alterations in colonic lymphocyte populations. The present studies indicate that NO produced by individual NOS isoforms plays different roles in modulating an inflammatory process.

inducible nitric oxide synthase; endothelial nitric oxide synthase; neuronal nitric oxide synthase; dextran sodium sulfate

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