Inhibition of TNF-α Improves Indomethacin-Induced Enteropathy in Rats by Modulating iNOS Expression
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TNF-α, including other proinflammatory cytokines alone or in combination, induces iNOS expression and upregulates inflammatory responses. We evaluated the relationship between TNF-α and iNOS expression in indomethacin-induced jejunoileitis in male Sprague–Dawley rats. Rats were fed a daily dose of a phosphodiesterase inhibitor—either theophylline or pentoxifylline—for 2 days. Jejunoileitis was induced with two subcutaneous injections of indomethacin (7.5 mg/kg) 24 hr apart and theophylline or pentoxifylline continued for 12 hr or 4 days. Other rats received a single intraperitoneal injection of anti-TNF-α monoclonal antibody (TNF-Ab) 30-min before indomethacin. At 4 days TNF-Ab, theophylline, or pentoxifylline treatment significantly decreased indomethacin-induced ulceration, myeloperoxidase activity, and disease activity index. Although indomethacin significantly increased serum TNF-α and nitrate/nitrite levels over the control value as early as 12 hr, iNOS expression was detected only after 4 days. Serum IL-1β level did not change at 12 hr but increased fourfold at 4 days. Treatment with TNF-Ab, theophylline, or pentoxifylline significantly reduced serum/tissue TNF-α, IL-1β, nitrate/nitrite, and iNOS expression. The downregulation of nitrate/nitrite by these inhibitors suggests that TNF-α modulates iNOS expression.
Keywordsanti-TNF-α antibody phosphodiesterase inhibitor nitric oxide synthase intestinal ulceration
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