title: Role of tumor necrosis factor alpha release and leukocyte margination in indomethacin-induced gastric injury in rats.
abstract: OBJECTIVE
  Several studies have shown that polymorphonuclear neutrophil leukocyte (PMN) margination is an early and critical event in the pathogenesis of gastric mucosal injury caused by nonsteroidal anti-inflammatory drugs. Tumor necrosis factor (TNF) alpha is a proinflammatory cytokine that causes PMN margination by up-regulating expression of adhesion molecules on both PMN and endothelial cells. This study investigated whether substances that modulate TNF synthesis and release influence PMN margination and indomethacin-induced gastric damage.
  
  
  METHODS
  Rats were treated with several doses of indomethacin alone or in association with substances known to increase (interleukin 2 and lipopolysaccharide) or inhibit (pentoxifylline, dexamethasone, granulocyte colony-stimulating factor [G-CSF]) TNF synthesis and release.
  
  
  RESULTS
  Indomethacin administration caused dose-dependent damage and increased PMN margination and plasma TNF concentrations. Pretreatment with interleukin 2 and lipopolysaccharide significantly increased TNF release, PMN margination, and gastric mucosal damage, but administration of dexamethasone, pentoxifylline, and G-CSF provided almost total protection. The administration of G-CSF alone caused a significant increase in gastric PMN margination but protected against the indomethacin-induced gastropathy.
  
  
  CONCLUSIONS
  Agents that regulate TNF synthesis and release influence gastric susceptibility to indomethacin by modulating PMN margination. G-CSF increased PMN infiltration but protected against the mucosal injury, suggesting that PMN margination alone is not sufficient to induce mucosal damage.
authors.affiliation: Dipartimento di Medicina Clinica, Farmacologia, e Patologia, Università degli Studi di Perugia, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Santucci
authors.forename: S
authors.initials: S
authors.lastname: Fiorucci
authors.forename: F M
authors.initials: FM
authors.lastname: Di Matteo
authors.forename: A
authors.initials: A
authors.lastname: Morelli
mesh_terms: D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D007213:Indomethacin; D007376:Interleukin-2 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008297:Male; D009504:Neutrophils; D010431:Pentoxifylline / Q000494:pharmacology*; D010434:Pepsin A / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D003907:Dexamethasone; D009195:Peroxidase; D010434:Pepsin A; D010431:Pentoxifylline; D007213:Indomethacin