AJP - Gastrointestinal and Liver Physiology, Vol 270, Issue 1 42-G48, Copyright © 1996 by American Physiological Society

ARTICLES

Tumor necrosis factor mediation of NSAID-induced gastric damage: role of leukocyte adherence

C. B. Appleyard, D. M. McCafferty, A. W. Tigley, M. G. Swain and J. L. Wallace
Intestinal Disease Research Unit, University of Calgary, Alberta, Canada.

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.

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