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Gastric damage and granulocyte infiltration induced by indomethacin in tumour necrosis factor receptor 1 (TNF-R1) or inducible nitric oxide synthase (iNOS) deficient mice

Lookup NU author(s): Dr Henrique De Paula Lemos

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Abstract

BACKGROUND:Tumour necrosis factor alpha (TNF-alpha) is involved in non-steroidal anti-inflammatory drug induced gastropathy. Nitric oxide (NO) is a mediator of gastrointestinal mucosal defence but, paradoxically, it also contributes to mucosal damage.AIMS:We optimised the C57BL/6 mouse model of indomethacin induced gastropathy to evaluate the role of TNF-alpha and inducible nitric oxide synthase (iNOS) generated NO in gastric damage and granulocyte infiltration using tumour necrosis factor receptor 1 (TNF-R1-/-) or iNOS (iNOS-/-) deficient mice.METHODS:Different doses of indomethacin (2.5, 5, 10, 20 mg/kg) were administered and animals were assessed 6, 12, or 24 hours later. Gastric damage was measured by the sum of all erosions in the gastric mucosa, and gastric granulocyte infiltration was determined by myeloperoxidase (MPO) activity. Other groups of wild-type mice received thalidomide, dexamethasone, fucoidin, L-NAME, or 1400W, and then indomethacin was administered. Additionally, indomethacin was administered to TNF-R1-/- or iNOS-/-. Gastric damage and MPO activity were evaluated 12 hours later.RESULTS:Indomethacin induced dose and time dependent gastric damage and increase in MPO activity in wild-type mice, with the greatest effect at a dose of 10 mg/kg and after 12 hours. Treatment with thalidomide, dexamethasone, or fucoidin reduced gastric damage and MPO activity induced by indomethacin. After indomethacin administration, TNF-R1-/- had less gastric damage and MPO activity than controls. Genetic (knockout mice) or pharmacological (1400W and L-NAME) inhibition of iNOS activity reduced indomethacin induced gastric damage, despite no reduction in MPO activity.CONCLUSION:TNF-alpha, acting via TNF-R1, is involved in indomethacin induced gastric damage and granulocyte infiltration. Furthermore, iNOS generated NO is involved in gastric damage induced by indomethacin.


Publication metadata

Author(s): Souza MH, Lemos HP, Oliveira RB, Cunha FQ

Publication type: Article

Publication status: Published

Journal: Gut

Year: 2004

Volume: 53

Issue: 6

Pages: 791-796

Print publication date: 01/06/2004

Online publication date: 11/05/2004

ISSN (print): 0017-5749

Publisher: BMJ Group

URL: http://doi.org/10.1136/gut.2002.012930

DOI: 10.1136/gut.2002.012930

PubMed id: 15138204


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