Antithrombin prevents reperfusion-induced hepatic apoptosis by enhancing insulin-like growth factor-I production in mice

Objective: Antithrombin (AT) reduces ischemia/reperfusion-induced liver injury by increasing release of calcitonin gene–related peptide (CGRP) from sensory neurons. Because CGRP increases the production of insulin-like growth factor-I (IGF-I), an antiapoptotic factor, it is possible that AT prevents apoptosis by increasing IGF-I production. We examined this possibility in the present study. Design: Prospective, randomized, controlled study. Setting: University laboratory. Subjects: Male C57BL/6 wild-type mice and αCGRP-deficient mice weighing 16–23 g. Interventions: AT (250 units/kg) was intravenously administered to mice subjected to hepatic ischemia/reperfusion. Liver injury was evaluated by determining changes in serum levels of alanine aminotransferase after ischemia/reperfusion. Hepatic apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining. Measurements and Main Results: AT reduced ischemia/reperfusion-induced liver injury and enhanced increases in hepatic tissue levels of IGF-I in wild-type mice, although it did not reduce liver injury or enhance increases in hepatic tissue levels of IGF-I in αCGRP-deficient mice. Reperfusion-induced hepatic apoptosis was markedly suppressed by AT in wild-type mice, but not in αCGRP-deficient mice. Pretreatment with anti-IGF-I antibody completely reversed therapeutic effects of AT in wild-type mice. Both CGRP and IGF-I showed therapeutic effects similar to those of AT in wild-type and αCGRP-deficient mice. Conclusions: These observations suggested that AT may prevent reperfusion-induced hepatic apoptosis by enhancing IGF-I production through promotion of sensory neuron activation, thereby reducing ischemia/reperfusion-induced liver injury.