Inhibition of TNF-α improves indomethacin-induced enteropathy in rats by modulating iNOS expression

• Published in: Digestive diseases and sciences 2005-09, Vol.50 (9), p.1677-1683
• Main Authors: SAUD, B, NANDI, J, ONG, G, FINOCCHIARO, S, LEVINE, R. A
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - toxicity; Antibodies, Monoclonal; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Down-Regulation; Ileitis - chemically induced; Ileitis - immunology; Ileitis - veterinary; Indomethacin - pharmacology; Indomethacin - toxicity; Inflammation; Jejunal Diseases - chemically induced; Jejunal Diseases - immunology; Jejunal Diseases - veterinary; Male; Medical sciences; Nitrates; Nitric Oxide Synthase - biosynthesis; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Nitrites; Pentoxifylline - administration & dosage; Pentoxifylline - pharmacology; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - administration & dosage; Phosphodiesterase Inhibitors - pharmacology; Rats; Rats, Sprague-Dawley; Theophylline - administration & dosage; Theophylline - pharmacology; Tumor Necrosis Factor-alpha - physiology; Up-Regulation
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1007/s10620-005-2914-0

TNF-alpha, including other proinflammatory cytokines alone or in combination, induces iNOS expression and upregulates inflammatory responses. We evaluated the relationship between TNF-alpha 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-alpha 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-alpha and nitrate/nitrite levels over the control value as early as 12 hr, iNOS expression was detected only after 4 days. Serum IL-1beta 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-alpha, IL-1beta, nitrate/nitrite, and iNOS expression. The downregulation of nitrate/nitrite by these inhibitors suggests that TNF-alpha modulates iNOS expression.