Pentoxifylline prevents concanavalin A-induced hepatitis by reducing tumor necrosis factor alpha levels and inhibiting adhesion of T lymphocytes to extracellular matrix.
OBJECTIVE
Concanavalin A activates T lymphocytes and causes T cell-mediated hepatic injury in mice. Tumor necrosis factor alpha is a critical mediator in this experimental model. T-cell-mediated liver injury involves the migration of immune cells, notably CD4+ T lymphocytes, into liver tissue. Pentoxifylline is a strong suppressor of tumor necrosis factor alpha release and prevents leukocyte adherence to vascular endothelium and down-regulates the expression of intercellular adhesion 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 12 mg/kg concanavalin A with or without a single injection of pentoxifylline (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 mice treated with concanavalin A only. We also assessed the effects of pentoxifylline on the adhesive properties of T lymphocytes to fibronectin, as a paradigm for immune cell-extracellular matrix interactions required for migration. Pretreatment with pentoxifylline significantly reduced serum levels of liver enzymes (3800+/-650 vs 150+/-28 IU/l) and tumor necrosis factor alpha (710+/-105 vs 113+/-15 pg/ml) with no evidence of inflammation in histopathologic examination compared to control mice treated with concanavalin A. Pentoxifylline also inhibited the binding of murine T cells to fibronectin. All the effects of pentoxifylline were dose-dependent.


CONCLUSIONS
These results indicate that high doses of pentoxifylline can prevent concanavalin A hepatitis by suppression of tumor necrosis factor alpha release and inhibition of T cells adhesion to extracellular matrix.
Department of Gastroenterology, The E. Wolfson Medical Center, Holon, Israel.
H
H
Shirin
R
R
Bruck
H
H
Aeed
D
D
Frenkel
G
G
Kenet
L
L
Zaidel
Y
Y
Avni
Z
Z
Halpern
R
R
Hershkoviz
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D003208:Concanavalin A; D005109:Extracellular Matrix; D005353:Fibronectins; D006520:Hepatitis, Animal / Q000097:blood* / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D007792:Lactulose / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010431:Pentoxifylline / Q000494:pharmacology*; D018124:Receptors, Tumor Necrosis Factor; D013601:T-Lymphocytes / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014665:Vasodilator Agents / Q000494:pharmacology*
D005353:Fibronectins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D003208:Concanavalin A; D007792:Lactulose; D010431:Pentoxifylline