Tumor necrosis factor mediation of NSAID-induced gastric damage: role of leukocyte adherence.
Neutrophil adherence to the vascular endothelium has been suggested to be a critical event in the pathogenesis of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric damage. Recently, increased plasma levels of tumor necrosis factor-alpha (TNF-alpha), which can increase leukocyte adherence, have been reported after administration of indomethacin. This study was performed to determine the relationship between plasma TNF-alpha levels, leukocyte adherence, and NSAID-induced gastric injury. Administration of indomethacin to rats resulted in a significant elevation of plasma TNF-alpha levels within 30 min and the development of gastric erosions. Pretreatment with dexamethasone and prostaglandin E2 almost completely prevented gastric injury and abolished the rise in plasma TNF-alpha. Pentoxifylline dose dependently reduced both gastric damage and plasma TNF-alpha. Similar effects were observed with three other TNF-alpha synthesis inhibitors and with an anti-TNF-alpha antisera. Pentoxifylline also significantly reduced the extent of antral ulceration induced by naproxen. However, pentoxifylline did not significantly affect indomethacin-induced leukocyte adherence. These results suggest that TNF-alpha plays a critical role in the pathogenesis of NSAID-induced gastric injury, but this cytokine may not be responsible for NSAID-induced leukocyte adherence.
Appleyard
C B
CB
Intestinal Disease Research Unit, University of Calgary, Alberta, Canada.
McCafferty
D M
DM
Tigley
A W
AW
Swain
M G
MG
Wallace
J L
JL
D000821:Animal Feed; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002448:Cell Adhesion; D002465:Cell Movement; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced / Q000473:pathology; D007213:Indomethacin; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D009288:Naproxen; D051381:Rats; D017208:Rats, Wistar; D013270:Stomach / Q000473:pathology; D013272:Stomach Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D014409:Tumor Necrosis Factor-alpha; D009288:Naproxen; D007213:Indomethacin