Increase in tumor necrosis factor‐α production linked to the toxicity of indomethacin for the rat small intestine

• Published in: British journal of pharmacology Vol. 124; no. 7; pp. 1385 - 1394
• Main Authors: Bertrand, Viviane, Guimbaud, Rosine, Tulliez, Micheline, Mauprivez, Cédric, Sogni, Philippe, Couturier, Daniel, Giroud, Jean‐Paul, Chaussade, Stanislas, Chauvelot‐Moachon, Laurence
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-08-1998; Nature Publishing
• Subjects: 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone - pharmacology; Animals; Anti-Inflammatory Agents, Non-Steroidal - toxicity; Biological and medical sciences; Digestive System - pathology; Drug toxicity and drugs side effects treatment; Indomethacin - toxicity; inducible NO synthase; intestinal inflammation; Jejunum - drug effects; Jejunum - metabolism; Jejunum - pathology; Male; Medical sciences; myeloperoxidase; nitric oxide; nonsteroidal anti‐inflammatory drugs; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - pharmacology; prostaglandins; Rats; Rats, Wistar; RO 20‐1724; small intestine; TNF‐α; Toxicity: digestive system; Tumor Necrosis Factor-alpha - biosynthesis; type IV phosphodiesterase inhibitors; Ulcer - chemically induced; Ulcer - prevention & control; Prostaglandin-endoperoxide synthase; Rat; Enzyme; Toxicity; Cytokine; Rodentia; Indometacin; Gut; Enzyme inhibitor; Inflammation; Non steroidal antiinflammatory agent; Vertebrata; Mammalia; Animal; Indoleacetic acid derivatives; Digestive diseases; Intestinal disease; Ulcer; Subcutaneous administration; Oxidoreductases; Mechanism of action; Tumor necrosis factor α
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0701968

1
The toxic effects of nonsteroidal anti‐inflammatory drugs for the lower gastrointestinal tract share certain features with inflammatory processes, suggesting that the release of inflammation cytokines such as TNF‐α may damage the intestine.
2
Rats received a s.c. injection of indomethacin. Then, jejunum‐ileum was taken up for the quantification of ulcerations, production of TNF‐α, nitrites and PGE2 ex vivo and activity of calcium‐independent NO synthase and myeloperoxydase. Activation of NO metabolism and myeloperoxydase were measured as potential effectors of TNF‐α.
3
Jejunum‐ileum from rats having received indomethacin (10 mg kg−1) produced TNF‐α ex vivo. Cytokine production was associated with the onset of macroscopic ulcerations of the small intestine, and preceded nitrite production and tissue activity of myeloperoxidase.
4
Similar intestinal ulcerations and upregulation of TNF‐α were obtained with flurbiprofen (30 mg kg−1), chemically unrelated to indomethacin.
5
TNF‐α production was proportional to the indomethacin dose (from 3–20 mg kg−1) and correlated with the surface area of ulcerations and nitrite production, 24 h after indomethacin administration.
6
Pretreatment of rats with RO 20‐1724, a type‐IV phosphodiesterase inhibitor which inhibits TNF‐α synthesis, substantially reduced jejunum‐ileum ulcerations, TNF‐α and nitrite production and tissue enzyme activities.
7
These findings provide evidence that TNF‐α is increased in indomethacin‐induced intestinal ulcerations and support suggestions that TNF‐α is involved at an early stage of nonsteroidal anti‐inflammatory drug toxicity for the small intestine.
British Journal of Pharmacology (1998) 124, 1385–1394; doi:10.1038/sj.bjp.0701968