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 alphaCGRP-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 alphaCGRP-deficient mice. Reperfusion-induced hepatic apoptosis was markedly suppressed by AT in wild-type mice, but not in alphaCGRP-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 alphaCGRP-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.