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来减轻再灌注诱导的肝损伤，但在CGRP敲除小鼠中不起作用，这表明AT可能通过增加感觉神经元的CGRP释放来减轻肝损伤。AT通过增加肝脏胰岛素样生长因子-I（IGF-1）的表达来减少再灌注诱导的肝细胞凋亡，IGF-1是一种能够抑制细胞凋亡的重要物质，但在CGRP敲除小鼠中并非如此。在野生型和CGRP敲除小鼠中，IGF-I的给药减少了再灌注诱导的肝细胞凋亡。因此，AT可能通过增加IGF-I的产生来防止肝细胞凋亡，从而减少再灌注诱导的肝损伤。CGRP在AT诱导的IGF-I产生增加中起关键作用。这些观察结果表明，AT可能减少再灌注诱导的肝损伤，不仅通过抑制凝血异常，但通过减轻炎症反应，通过促进感觉神经元激活。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的发展中起关键作用，AT可能通过促进感觉神经元激活导致IGF-I产生增加来改善严重脓毒症患者的结果，

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,