Antithrombin Attenuates Microvascular Leakage and Leukocyte-Endothelial Interaction in Response to Endotoxin

Antithrombin (AT), formerly referred to as ATIII, is the most important inhibitor of thrombin in plasma and a member of the serine protease inhibitor family that also exerts an inhibitory effect on other coagulation factors and serine proteases.[1] AT levels have been shown to be reduced in conditions such as sepsis or the systemic inflammatory response syndrome in combination with shock or disseminated intravascular coagulation (DIC), or both.[2] [3] Therapeutic substitution of AT concentrate has been shown to ameliorate the severity of multiple organ failure and DIC in critically ill patients, but available data indicate that it does not significantly reduce mortality in individuals with severe sepsis.[4] [5] Numerous studies in animal models of sepsis have shown a beneficial effect of AT supplementation on DIC or mortality, or both.[6] Despite the large body of experimental data, the mechanism(s) underlying these actions is not completely understood. However, it is believed that at least some effects of AT may be explained by its anticoagulatory actions. Recent results have suggested that AT may also have significant anti-inflammatory actions independent of its effects on coagulation.[7] [8] Uchiba and coworkers[9] described a possible effect of AT on microvascular permeability and the accumulation of leukocytes within the microcirculation of the lung during endotoxemia.

Activation of polymorphonuclear leukocytes leads to adhesion to vascular endothelial cells and release of proteases and oxygen radicals, followed by derangement of endothelial function. This process is an integral part of the inflammatory reaction.[10] [11] As a result, permeability of the microvasculature may increase, with consequent fluid loss and interstitial edema.[12] This may lead to impaired diffusion of oxygen and a perfusion failure of the microcirculation. The resultant hypoxia, depletion of energy stores, and damage to parenchymal cells could contribute to the development of multiple organ failure.[13] [14] [15]

In this study, we attempted to increase our understanding of the effects of human AT by evaluating the effects of supplementation of this serine protease inhibitor in endotoxin (lipopolysaccharide [LPS])-challenged rats. Intravital videomicroscopy was used to investigate the effects of AT on microvascular protein leakage and adherence of leukocytes to mesenteric venules.

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