PENTOXIFYLLINE PREVENTS CONCANAVALIN A-INDUCED HEPATITIS BY REDUCING TUMOR-NECROSIS-FACTOR-ALPHA LEVELS AND INHIBITING ADHESION OF T-LYMPHOCYTES TO EXTRACELLULAR-MATRIX

Background/Aims: ConcanavaIin A activates T lymphocytes and causes T c ell-mediated hepatic injury in mice. Tumor necrosis factor alpha is a critical mediator in this experimental model. T-cell-mediated liver in jury involves the migration of immune cells, notably CD4(+) T lymphocy tes, into liver tissue. Pentoxifylline is a strong suppresser of tumor necrosis factor a release and prevents leukocyte adherence to vascula r endothelium and down-regulates the expression of intercellular adhes ion molecule-1 in monocytes. In this study we examined the efficacy of pentoxifylline as a potential therapeutic compound for the treatment of concanavalin A hepatitis. Methods: Balb/c mice were injected with 1 2 mg/kg concanavalin A with or without a single injection of pentoxify lline (5-300 mg/kg), 2 h prior to concanavalin A administration. Liver damage was evaluated by determining serum levels of liver enzymes and tumor necrosis factor alpha, and hepatic histopathology compared to m ice treated with concanavalin A only. We also assessed the effects of pentoxifylline on the adhesive properties of T lymphocytes to fibronec tin, as a paradigm for immune cell-extracellular matrix interactions r equired for migration. Results: Pretreatment with pentoxifylline signi ficantly reduced serum levels of liver enzymes (3800+/-650 vs 150+/-28 IU/I) and tumor necrosis factor alpha (710+/-105 vs 113+/-15 pg/ml) w ith no evidence of inflammation in histopathologic examination compare d to control mice treated with concanavalin A. Pentoxifylline also inh ibited the binding of murine T cells to fibronectin. All the effects o f pentoxifylline were dose-dependent. Conclusions: These results indic ate that high doses of pentoxifylline can prevent concanavalin A hepat itis by suppression of tumor necrosis factor alpha release and inhibit ion of T cells adhesion to extracellular matrix.