Antithrombin reduces ischemia/reperfusion-induced liver injury in rats by activation of cyclooxygenase-1

Summary

This study was conducted to determine which isoform of cyclooxygenase (COX) is more significantly involved in the antithrombin (AT)-induced increase in prostaglandin production in the liver of rats, subjected to hepatic ischemia/reperfusion (I/R). Hepatic tissue levels of 6-keto-PGF_1α, a stable metabolite of prostacyclin (PGI₂), and PGE₂ were transiently increased 1 hour after reperfusion. Thereafter, hepatic PGE₂ levels were gradually increased until 6 hours after reperfusion, while hepatic 6-keto-PGF_1α levels were decreased to the pre-ischemia levels at 6 hours after reperfusion. AT significantly enhanced increases in hepatic tissue levels of 6-keto-PGF_1α and PGE₂ seen 1 hour after reperfusion, while it inhibited increases in hepatic PGE₂ levels seen 6 h after reperfusion. Neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT which lacks affinity for heparin, showed any effects on these changes. Pretreatment with indomethacin (IM), a non-selective inhibitor of COX, inhibited AT-induced increases in hepatic tissue levels of 6-keto-PGF_1α and PGE₂ seen 1 hour after reperfusion, whereas pretreatment with NS-398, a selective inhibitor of COX-2, did not. The increase in hepatic tissue blood flow and inhibition of hepatic inflammatory responses seen in animals given AT were reversed by pretreatment with IM, but were not affected by pretreatment with NS-398. Administration of iloprost, a stable analog of PGI₂, and PGE₂ produced effects similar to those induced by AT. Increases in hepatic tissue levels of PGE₂ 6 hours after reperfusion were inhibited by pretreatment with NS-398. Although AT did not affect COX-1 mRNA levels 1 hour after reperfusion, it inhibited the I/R-induced increases in hepatic tissue levels of both PGE₂ and COX-2 mRNA 6 hours after reperfusion. These observations strongly suggested that AT might reduce the I/R-induced liver injury by increasing the production of PGI₂ and PGE₂ through activation of COX-1. Furthermore, since TNF-a is capable of inducing COX-2, inhibition of TNF-a production by AT might inhibit COX-2-mediated PGE₂ production. These effects induced by AT might contribute to its anti-inflammatory activity.

Keywords

Antithrombin - ischemia/reperfusion - liver - cyclooxygenase - PGE₂ - prostacyclin

• References

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