Possible therapeutic application of ntithrombin in severe sepsis

抗凝血酶(AT)通过促进野生型小鼠感觉神经元的激活而减轻再灌流所致的肝损伤，但对CGRP基因敲除小鼠无此作用，提示AT可能通过增加感觉神经元释放CGRP来减轻肝损伤。AT通过增加肝脏胰岛素样生长因子-1(IGF-1)的表达来减少再灌流诱导的肝细胞凋亡，IGF-1是一种重要的抑制细胞凋亡的物质，但在CGRP基因敲除的小鼠中不能。给予IGF-I可减少野生型和CGRP基因敲除小鼠再灌流诱导的肝细胞凋亡。因此，AT可能通过增加IGF-I的产生来阻止肝细胞凋亡，从而减轻再灌流所致的肝损伤。CGRP在AT诱导的IGF-I分泌增加中起关键作用。这些观察表明，AT可能不仅通过抑制凝血功能异常而减轻再灌流所致的肝损伤，而且可能通过促进感觉神经元的激活来减轻炎症反应。由于组织细胞和淋巴细胞的凋亡在严重脓毒症的病理状态发展中起关键作用，AT可能通过促进感觉神经元的激活而增加IGF-I的产生，从而改善严重脓毒症患者的预后。

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,