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(American Journal of Pathology. 2007;170:490-496.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060594

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

Christian F. Krieglstein*, Christoph Anthoni*{dagger}, Wolfgang H. Cerwinka{ddagger}, Karen Y. Stokes{dagger}, Janice Russell{dagger}, Matthew B. Grisham{dagger} and D. Neil Granger{dagger}

From the Department of General Surgery,* Westfalian Wilhelm’s University, Muenster, Germany; the Department of Molecular and Cellular Physiology,{dagger} Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana; and the Department of Urology,{ddagger} University of Miami Miller School of Medicine, Miami, Florida

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{Rightarrow}WT bone marrow chimeras with normal iNOS function; 3) WT{Rightarrow}iNOS–/– chimeras (with functional blood cell iNOS, but iNOS-deficient tissue); 4) iNOS–/–{Rightarrow}WT chimeras (with iNOS-deficient blood cells, but normal tissue iNOS activity); and 5) iNOS-deficient mice. In WT mice and WT{Rightarrow}WT chimeras, DSS-induced colonic inflammation was characterized by bloody diarrhea and a high disease activity index. However, WT{Rightarrow}iNOS–/– and iNOS–/–{Rightarrow}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{Rightarrow}WT chimeras (29.0 ± 1), whereas MPO was significantly reduced in iNOS–/– mice and iNOS–/–{Rightarrow}WT chimeras (9.5 ± 1.7 and 15.6 ± 2.2, respectively). WT{Rightarrow}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.





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