ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA RELEASE AND LEUKOCYTE MARGINATIONIN INDOMETHACIN-INDUCED GASTRIC INJURY IN RATS

Background/Aims: Several studies have shown that polymorphonuclear neu trophil 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) or is a proinflammato ry cytokine that causes PMN margination by up-regulating expression of adhesion molecules on both PMN and endothelial cells. This study inve stigated whether substances that modulate TNF synthesis and release in fluence PMN margination and indomethacin-induced gastric damage. Metho ds: Rats were treated with several doses of indomethacin alone or in a ssociation with substances known to increase (interleukin 2 and lipopo lysaccharide) or inhibit (pentoxifylline, dexamethasone, granulocyte c olony-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 inte rleukin 2 and lipopolysaccharide significantly increased TNF release, PMN margination, and gastric mucosal damage, but administration of dex amethasone, pentoxifylline, and G-CSF provided almost total protection . The administration of G-CSF alone caused a significant increase in g astric PMN margination but protected against the indomethacin-induced gastropathy. Conclusions: Agents that regulate TNF synthesis and relea se influence gastric susceptibility to indomethacin by modulating PMN margination. G-CSF increased PMN infiltration but protected against th e mucosal injury, suggesting that PMN margination alone is not suffici ent to induce mucosal damage.