abstrakt w j. angielskim: |
We have recently demonstrated that concanavalin A (Con A)-induced hepatitis is associated with the release of endogenous 1-methylnicotinamide (MNA). Here we study the mechanism by which exogenous MNA alleviates Con A-induced liver inflammation and injury in vivo. The involvement of prostacyclin ($PGI_{2}$) in hepatoprotective action of MNA (30-100 mg $kg^{-1}$; i.v.) was studied by the use of IP receptor antagonist RO3244794 (10 mg $kg^{-1}$; p.o.) given prior to Con A (5-20 mg $kg^{-1}$; i.v.). Liver damage was assessed by measurements of: liver specific transaminases in plasma (alanine aminotransferase; aspartate aminotransferase); cytokines release (IL-4, $IFN-\gamma$ and $TNF-\alpha$); liver histopathology; and 24 h survival rates. Additionally, the effect of a stable analog of prostacyclin (carbaprostacyclin) on IL-4, $IFN-\gamma$ and $TNF-\alpha$ production by isolated spleen lymphocytes in response to Con A was analyzed. MNA diminished Con A-induced rise in liver specific transaminases, alleviated histopathological injury and improved 24 h survival rates, the latter effect in a degree comparable with the pretreatment of animals with dexamethasone (0.5 mg $kg^{-1}$; i.p.). MNA inhibited also a rise in IL-4 and $TNF-\alpha$ concentration in plasma measured 2 h after Con A administration, while $IFN-\gamma$ was less affected. The effects of MNA were reversed by pretreatment with IP antagonist RO3244794. In isolated spleen lymphocytes, carbaprostacyclin profoundly decreased production of IL-4, the effect on $TNF-\alpha$ was modest with no effect on $IFN-\gamma$ production. In conclusion, MNA attenuated Con A-induced hepatitis by a prostacyclin-dependent mechanism involving the inhibition of lymphocytes-derived IL-4 and the inhibition of Kuppfer-cells derived $TNF-\alpha$. |
słowa kluczowe w j. angielskim: |
1-methylnicotynamide, concanavalin A, IL-4, murine hepatic injury, prostacyclin, 1-methylnicotinamide, alanine aminotransferase, aspartate aminotransferase, carbacyclin, concanavalin A, dexamethasone, gamma interferon, interleukin 4, prostacyclin, prostaglandin receptor blocking agent, tumor necrosis factor alpha, alanine aminotransferase blood level, animal cell, animal experiment, animal model, animal tissue, article, aspartate aminotransferase blood level, controlled study, cytokine production, drug mechanism, histopathology, Kupffer cell, liver histology, liver injury, liver protection, mouse, nonhuman, priority journal, spleen lymphocyte, survival rate |