Possible therapeutic application of ntithrombin in severe sepsis

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Antithrombin (AT) reduces reperfusion-induced liver injury by promoting sensory neuron activation in wild-type mice, but not in CGRP-knockout mice, suggesting that AT might reduce the liver injury by increasing CGRP release from sensory neurons,. AT reduces the reperfusion-induced hepatic apoptosis by increasing the hepatic expression of insulin-like growth factor-I (IGF-1), an important substance capable of inhibiting apoptosis, but not in CGRP-knockout mice. Administration of IGF-I reduces the reperfusion-induced hepatic apoptosis in wild-type and CGRP-knockout mice. Thus, it is possible that AT reduces the reperfusion-induced liver injury by prevention of hepatic apoptosis through an increase in IGF-I production. CGRP plays a critical role in the AT-induced increase in IGF-I production. These observations suggest that AT might reduce the reperfusion-induced liver injury not only by inhibiting coagulation abnormalities, but by attenuating inflammatory responses through promotion of sensory neuron activation. Since apoptosis of tissue cells and lymphocytes are critically involved in the development of the pathologic condition of severe sepsis, AT might improve the outcome of patients with severe sepsis by promoting sensory neuron activation leading to an increase in IGF-I production,