Role of tumor necrosis factor alpha release and leukocyte margination in indomethacin-induced gastric injury in rats.
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.
Santucci
L
L
Dipartimento di Medicina Clinica, Farmacologia, e Patologia, Università degli Studi di Perugia, Italy.
Fiorucci
S
S
Di Matteo
F M
FM
Morelli
A
A
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*
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