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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

The Nitric Oxide Donor LA-419 [S-(6-Nitro-oxi-hexahydro-furo[3,2-b]furan-3-1-il)thioacetate] Prevents Intestinal Dysmotility, Bacterial Translocation, and Inflammation in a Rat Model of Enteritis

Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain (M.P., M.T.M., E.T., P.V.); and Research and Development, Lácer S. A., Barcelona, Spain (M.M.)

Indomethacin induces a chronic model of inflammatory bowel disease (IBD) characterized by spontaneous relapses of inflammation, bacterial translocation, and long-lasting motor disturbances derived from cyclical up-regulated inducible nitric-oxide synthase (iNOS) and sustained down-regulated neuronal NOS (nNOS). The aims of this study were to evaluate whether LA-419 [S-(6-nitro-oxi-hexahydro-furo[3,2-b]furan-3-1-il)thioacetate], a NO-donor drug, could re-establish the normal expression of NOS and, hence, prevent the development of intestinal dysmotility, bacterial translocation, and relapses of inflammation associated to this model. Enteritis was induced in rats by administration of indomethacin with and without treatment with a novel NO-donor: LA-419 (0.5 mg/ml in the drinking water). Inflammatory reaction was evaluated by measuring blood leukocytes, serum tumor necrosis factor, and tissue myeloperoxidase. Intestinal motor activity was evaluated using strain-gauges. Ileal expression of iNOS and nNOS mRNA was determined by reverse transcription-polymerase chain reaction. Bacterial translocation was evaluated in cultures from mesenteric lymph nodes. The indomethacin-induced acute inflammatory reaction was associated with a rise in blood leukocytes and tumor necrosis factor. In the chronic stage, blood leukocyte monitoring allowed the selection of animals in active and inactive phases. Active phase was associated with iNOS up-regulation, high myeloperoxidase levels, hypomotility, and bacterial translocation. In contrast, inactive phase was associated with hypermotility and absence of bacterial translocation. LA-419 treatment restored nitric-oxide synthase isoenzyme expression and prevented the oscillation of both inflammatory and motor parameters that could be cyclically observed in inflamed rats. LA-419 also prevented intestinal dysmotility, bacterial translocation, and relapses of intestinal inflammation. LA-419 might be a novel therapeutic approach to prevent acute inflammatory relapses in patients with IBD.

Address correspondence to. Maria Teresa Martín, Unidad de Fisiología, Facultad de Veterinaria, Universidad Autónoma de Barcelona 08193, Bellaterra, Spain. E-mail: maite.martin{at}uab.es