title: Gastric damage and granulocyte infiltration induced by indomethacin in tumour necrosis factor receptor 1 (TNF-R1) or inducible nitric oxide synthase (iNOS) deficient mice.
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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza-CE, Brazil. souzamar@ufc.br
authors.forename: M H L P
authors.initials: MH
authors.lastname: Souza
authors.forename: H Paula
authors.initials: HP
authors.lastname: Lemos
authors.forename: R B
authors.initials: RB
authors.lastname: Oliveira
authors.forename: F Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000578:Amidines / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D001596:Benzylamines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005753:Gastric Mucosa; D006098:Granulocytes / Q000187:drug effects*; D007213:Indomethacin / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000172:deficiency*; D052247:Nitric Oxide Synthase Type II; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency*; D013272:Stomach Diseases / Q000139:chemically induced*
chemical_list: D000578:Amidines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001596:Benzylamines; D004791:Enzyme Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D018124:Receptors, Tumor Necrosis Factor; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin