Antithrombin (AT) improves inflammation induced microcirculatory disturbance in rat mesentery

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Background

Impairment of the microcirculation is one of the main causes for multiple organ failure (MOF) in critical care patients. Trials with AT substitution in patients with sepsis showed a positive effect on the development and course of MOF. Recent experimental studies indicate that there might be specific AT-effects independent of the coagulation cascade, which can modulate endothelial-leukocyte interaction and vascular permeability.

Methods

The effect of AT substitution on LPS-induced microvascular leakage (ML) and leukocyte adhesion (LA) in the rat mesentery was investigated by means of intravital microscopy. Male CD rats were infused with 0.5 mg/kg LPS (E. coli) over 80 min. Vascular leakage was detected with FITC-marked rat serum albumin by fluorescence microscopy and evaluated by grey-value analysis with image processing software. Light microscopy was used to evaluate leukocytes adherence to the vessel wall. Two treated groups received 500 U/kg AT either 20 min prior to or 20 min after the beginning of LPS-infusion. Animals not infused with LPS, either untreated or treated with placebo (albumin), served as controls. One pre-treated group additionally received heparin at a clinically used dosage. Furthermore, interleukin-2 (IL-2) was used to induce ML and treated with AT prior to infusion.

Results

LPS-infusion led to a significant increase of ML and LA compared to controls. Both effects were reduced to the level of controls by the substitution of AT. No significant differences were found between the pre-treated or the post-treated group. IL-2 induced ML was also reduced by treatment with AT.

Conclusion

Substitution of AT, even when given after LPS, ameliorates vascular leakage and leukocyte adhesion to the vessel wall. Together, these effects improve flow conditions in the microcirculation. Hence IL-2-induced leakage could also be modulated by AT and a direct effect by AT on leukocyte adhesion seems to be likely.