Unabhängig vom Ort der iNOS Expression ist iNOS-abhängiges NO ein zentraler Vermittler der Entzündungsreaktion im DSS-Colitis Modell der Maus

Abstract

Several studies have suggested that iNOS-derived NO may modulate some pathologic changes associated with IBD [1, 2]. The aims were: (1) To examine the importance of inducible nitric oxide (iNOS) expression in the development of experimental colitis and (2) to assess the influence of tissue-specific iNOS expression on neutrophil recruitment in inflamed colons. Study groups included: (A) Wild-type (C57/BL6); (B) WT → WTchimeras with normal iNOS function; (C) WT → iNOS^-/- chimeras (produced by bone marrow transplant) with functional blood cell iNOS, but iNOS deficient (^-/-) tissue; (D) iNOS^-/- → WT chimeras with iNOS deficient blood cells, but normal tissue iNOS activity; and (E) iNOS-deficient mice. Colitis was induced by replacing drinking water with dextran sulphate sodium (DSS) 2.5% over 7 days. Severity of colitis was assessed by a clinical disease activity index (DAI); while colonic injury was quantified using colon length and a histologic damage score. Neutrophil recruitment was indirectly monitored by mesuring colonic myeloperoxidase activity (MPO). In WT mice and WT → WT chimeras, DSS induced colitis was characterized by bloody diarrhea and high DAI values. However, WT → iNOS^-/-, iNOS^-/- → WT chimeras and iNOS^-/- mice exhibited attenuated disease severity with blunted gross rectal bleeding and significantly lower DAI scores. Colon length and histopathology paralleled clinical signs of inflammation. MPO-activity was equally high in WT mice (30.1 ± 1.7) and WT → WT chimeras (29.0 ± 1), whereas MPO-levels in iNOS^−/− mice and iNOS^−/− → WT chimeras were significantly reduced (9.5 ± 1.7 and 15.6 ± 2.2, respectively). The lowest colonic MPO activity was detected in WT → iNOS^−/− chimeras (3.7 ± 0.6). Our findings implicate a role for both blood cell- and tissue-derived NO in the pathogenesis of DSS-induced colitis, with tissue-associated iNOS contributing more significantly to neutrophil recruitment associated with colitis.