New Aspects of Antiinflammatory Activity of Antithrombin: Molecular Mechanism(s) and Therapeutic Implications

Abstract

Antithrombin (AT), an important natural anticoagulant, has been shown to reduce various organ failures as well as coagulation abnormalities in animal sepsis models and in patients with severe sepsis. Proinflammatory cytokines, such as tumor necrosis factor (TNF), play critical roles in the development of the multiple organ failure including disseminated intravascular coagulation by inducing endothelial cell injury through neutrophil activation during sepsis. AT increases the endothelial production of prostacyclin, a potent inhibitor of TNF production, thereby attenuating inflammatory responses in experimental animals given endotoxin and in those subjected to organ ischemia/reperfusion. AT increases the endothelial production of prostacyclin via promotion of calcitonin gene-related peptide (CGRP) release from sensory neurons. CGRP has been shown to increase the production of insulin-like growth factor-I (IGF-I), a potent antiapoptotic factor, in various organs in mice. AT increases IGF-I production via enhancing sensory neuron activation, thereby preventing reperfusion-induced hepatic apoptosis in mice. Because IGF-I has various important biological activities, such as promoting differentiation of various cell types and an anabolic effect in addition to potent antiapoptotic activity, AT might exert novel biological activities other than anticoagulant activities by promoting IGF-I production. These functional properties of AT might explain at least in part its therapeutic efficacy in patients with severe sepsis.