sodium-nitrite and Colitis--Ulcerative

Inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis are chronic inflammatory disorders of the intestinal tract with excessive production of cytokines, adhesion molecules, and reactive oxygen species. Although nitric oxide (NO) is reported to be involved in the onset and progression of IBDs, it remains controversial as to whether NO is toxic or protective in experimental colitis. We investigated the effects of oral nitrite as a NO donor on dextran sulfate sodium (DSS)-induced acute colitis in mice. Mice were fed DSS in their drinking water with or without nitrite for up to 7days. The severity of colitis was assessed by disease activity index (DAI) observed over the experimental period, as well as by the other parameters, including colon lengths, hematocrit levels, and histological scores at day 7. DSS treatment induced severe colitis by day 7 with exacerbation in DAI and histological scores. We first observed a significant decrease in colonic nitrite levels and increase in colonic TNF-alpha expression at day 3 after DSS treatment, followed by increased colonic myeloperoxidase (MPO) activity and increased colonic expressions of both inducible NO synthase (iNOS) and heme oxygenase-1 (HO-1) at day 7. Oral nitrite supplementation to colitis mice reversed colonic nitrite levels and TNF-alpha expression to that of normal control mice at day 3, resulting in the reduction of MPO activity as well as iNOS and HO-1 expressions in colonic tissues with clinical and histological improvements at day 7. These results suggest that oral nitrite inhibits inflammatory process of DSS-induced experimental colitis by supplying nitrite-derived NO instead of impaired colonic NOS activity.

Topics: Analysis of Variance; Animals; Blood Pressure; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Heart Rate; Hematocrit; Heme Oxygenase-1; Histocytochemistry; Male; Methemoglobin; Mice; Mice, Inbred ICR; Nitrates; Nitric Oxide Synthase Type II; Nitrites; Peroxidase; Sodium Nitrite; Specific Pathogen-Free Organisms; Tumor Necrosis Factor-alpha

Attempts were made to define which fatty acid (2:0 to 18:1) was optimally oxidized by isolated colonocytes (colonic epithelial cells) and to select inhibitors of fatty acid oxidation which would be analogous in their action to the inhibition of fatty acid oxidation observed in colonocytes involved with ulcerative colitis. Isolated colonic epithelial cells of Sprague-Dawley rats were used with 2-mercaptoacetate, dichloroacetate, 3-mercaptopropionate, 4-mercaptobutyrate, 4-sulfatebutyrate, 2-bromobutyrate, sulfite ions and nitrite ions. n-Butyrate (4:0) was maximally oxidized to CO2 and ketone bodies (mean value 5.46 mumols/min/g dry wt). Oxidation of butyrate to CO2 was diminished by 2-bromobutyrate, sulfite ions and all mercapto fatty acids. Both fatty acid oxidation and glucose oxidation were significantly inhibited by 2-bromobutyrate, while mercapto fatty acids and sulfite inhibited fatty acid oxidation (p less than 0.01) without significantly changing glucose oxidation. Observation with 2-mercaptoacetate and sulfite correlate with early changes of fatty acid oxidation observed in cases of ulcerative colitis, and warrant further study with isolated colonocytes of man.

Topics: 3-Mercaptopropionic Acid; Animals; Butyrates; Butyric Acid; Carbon Dioxide; Colitis, Ulcerative; Colon; Epithelium; Fatty Acids; Glucose; Ketone Bodies; Oxidation-Reduction; Rats; Rats, Inbred Strains; Sodium Nitrite; Sulfites; Thioglycolates

The therapeutic efficacy of salicylate drugs for ulcerative colitis in vivo is related to the capacity of each drug to suppress fatty acid oxidation in colonocytes in vitro. The suppression index of fatty acid oxidation (SIFO) was assessed with 17 salicylate drugs of either known or unknown therapeutic efficacy. The high SIFO value of 5-aminosalicylic acid (5-ASA) was reduced to zero when the amino group was replaced with a methyl, nitro, hydroxyl or bromine group. The SIFO of 3-ASA was dose-related and 2- to 3-fold greater than the SIFO of 5-ASA. The antioxidants methyl- or propyl-4-hydroxybenzoate have a high SIFO, but show a 'toxic' action towards colonocytes not observed with 3-ASA, 4-ASA or 5-ASA. A new cellular action proposed for 5-ASA is that acetylation of the amino group of 5-ASA in colonocytes releases free CoA countering sequestration of CoA observed in epithelial cells during active colitis.

Topics: Aminosalicylic Acids; Animals; Carbon Dioxide; Colitis, Ulcerative; Colon; Epithelial Cells; Fatty Acids; Mesalamine; Oxidation-Reduction; Rats; Rats, Inbred Strains; Salicylates; Sodium Nitrite