Role of Blood- and Tissue-Associated Inducible Nitric-Oxide Synthase in Colonic Inflammation

There is evidence that inducible nitric-oxide synthase (iNOS)-derived NO contributes to the pathophysiology of intestinal inflammation. The aims of this study were to assess the role of iNOS in the development of dextran sodium sulfate (DSS)-induced colonic inflammation and to define the contribution of tissue-specific iNOS expression to this inflammatory response. Study groups included: 1) wild-type (WT) mice; 2) WT⇒WT bone marrow chimeras with normal iNOS function; 3) WT⇒iNOS−/− chimeras (with functional blood cell iNOS, but iNOS-deficient tissue); 4) iNOS−/−⇒WT chimeras (with iNOS-deficient blood cells, but normal tissue iNOS activity); and 5) iNOS-deficient mice. In WT mice and WT⇒WT chimeras, DSS-induced colonic inflammation was characterized by bloody diarrhea and a high disease activity index. However, WT⇒iNOS−/− and iNOS−/−⇒WT chimeras and iNOS−/− mice exhibited an attenuated disease activity index, with parallel changes in histopathology. Colonic myeloperoxidase (MPO) was comparably elevated in DSS-treated WT mice (30.1 ± 1.7) and WT⇒WT chimeras (29.0 ± 1), whereas MPO was significantly reduced in iNOS−/− mice and iNOS−/−⇒WT chimeras (9.5 ± 1.7 and 15.6 ± 2.2, respectively). WT⇒iNOS−/− chimeras exhibited the lowest MPO activity (3.7 ± 0.6). Our findings implicate both blood cell- and tissue-derived iNOS in DSS-induced colonic inflammation, with tissue-associated iNOS making a larger contribution to the recruitment of inflammatory cells.