Antithrombin III prevents concanavalin A-induced liver injury through inhibition of macrophage inflammatory protein-2 release and production of prostacyclin in mice.
OBJECTIVE
Recently, we have reported that macrophage inflammatory protein-2 (MIP-2) plays a pivotal role in concanavalin A (Con A)-induced liver injury. In this study, we investigated the effect of antithrombin III (AT-III) on liver damage, and production of MIP-2 and prostacyclin in this model.


METHODS
Liver injury was induced by intravenous injection of Con A (15 mg/kg) and AT-III was administered (50, 250 and 500 units/kg, iv) 30 mm before Con A injection. Plasma levels of alanine aminotransferase (ALT), MIP-2 and 6-keto-prostaglandin F1alpha (6k-PG-F1alpha), stable metabolite of prostaglandin I(2) (prostacyclin), were determined.


RESULTS
The elevated plasma ALT levels 8, 16, 24 h after Con A injection were inhibited by AT-III pretreatment. The elevated plasma MIP-2 levels were significantly inhibited by AT-III pretreatment compared with vehicle treatment. The inhibitory effect of AT-III on plasma ALT and MIP-2 in Con A-induced liver injury was attenuated by indomethacin (5 mg/kg, ip). Plasma concentration of 6k-PG-F1alpha at 2 h after AT-III injection was significantly elevated compared with baseline and vehicle pretreatment.


CONCLUSIONS
These findings suggest that AT-III prevents Con A-induced liver injury through an inhibition of MIP-2 release and a production of prostacyclin.
Nakamura
Kimihide
K
Second Department of Internal Medicine, Asahikawa Medical College, Midorigaoka Higashi 2-1-1-1, Asahikawa 078-8510, Japan. kimihide@asahikawa-med.ac.jp
Ito
Taku
T
Yoneda
Masashi
M
Takamoto
Shujiro
S
Nakade
Yukiomi
Y
Okamoto
Satoshi
S
Okada
Mitsuyoshi
M
Yokohama
Shiro
S
Aso
Kazunobu
K
Makino
Isao
I
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000990:Antithrombin III / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism*; D003208:Concanavalin A; D016207:Cytokines / Q000096:biosynthesis; D011464:Epoprostenol / Q000096:biosynthesis* / Q000097:blood; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D008107:Liver Diseases / Q000188:drug therapy* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D015846:Monokines / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D015846:Monokines; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D000990:Antithrombin III; D011464:Epoprostenol; D000410:Alanine Transaminase; D007213:Indomethacin