PENTOXIFYLLINE PREVENTS INDOMETHACIN-INDUCED ACUTE GASTRIC-MUCOSAL DAMAGE IN RATS - ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA

Neutrophil adherence within the gastric microcirculation is thought to be a major step in the pathogenesis of gastric mucosal damage induced by indomethacin. Pentoxifylline, a methylxanthine derivative, prevent s leukocyte adherence to vascular endothelium and protects organs from shock by reducing tumour necrosis factor alpha (TNF alpha) concentrat ions. Rats were treated with 20 mg/kg oral indomethacin, pretreated wi th vehicle or with four different doses of pentoxifylline intraperiton eally,, and killed after three hours. The gross gastric mucosal injury , neutrophil margination into the gastric microcirculation, mucosal co ncentrations of 6-keto-prostaglandin F-1 alpha, (PGF(1 alpha)), and PG E(2) and serum TNF alpha values were measured. Whether the pentoxifyll ine induced protection involved nitric oxide mediated pathways or gast ric acid secretion was evaluated. The data indicate that pentoxifyllin e reduces indomethacin induced mucosal damage and neutrophil marginati on in a dose dependent manner without exerting any effect on gastric m ucosal prostaglandin concentrations. The maximally effective dose (200 mg/kg) of pentoxifylline reduced gastric damage by 90% and slightly s timulated acid secretion. The effect of pentoxifylline was not affecte d by pretreatment with the nitric oxide inhibitor. Pentoxifylline prev ented the indomethacin induced increase in TNF alpha concentrations in a dose dependent fashion. Serum TNF alpha values were 30.5 (7.0) IU/m l (mean (SEM)) in rats treated with indomethacin alone and 5.0 (2.5) I U/ml (p<0.01) in rats treated with indomethacin plus 200 mg/kg pentoxi fylline. Pentoxifylline, therefore, the acute gastric mucosal and neut rophil margination induced by indomethacin and reduces indomethacin in duced release of TNF alpha.