Publikationsdatum:
2006-11-16
Beschreibung:
Background: A phase III trial of antithrombin (AT) in sepsis showed benefit only in patients who did not receive concurrent heparin. We have shown that some of the beneficial effects of AT on leukocyte-endothelial (LE) interactions in sepsis models requires the activity of heparan sulfate 3-O-sulfotransferase-1 (3-OST-1), the enzyme that is responsible for the rate-limiting step in the biosynthesis of anticoagulant heparan sulfate. Fondiparinux (FOND) is a pharmacological agent that mimics the anticoagulant heparan sulfate pentasaccharide sequence synthesized by 3-OST-1. Objectives: We hypothesized that FOND treatment would alter LE interactions in sepsis models in mice, and AT effects in these models. Methods: Using intravital microscopy, we evaluated the effects of proinflammatory stimuli on leukocyte rolling and firm adhesion in post-capillary venules, and extravasation, into the cremaster muscle in live C57BL/6 mice. Human AT (0.25 U/g Thrombate III), and/or heparanoid or vehicle was infused intravenously prior to proinflammatory stimuli. Venules were chosen such that in all comparisons, the average diameter (range 20 to 50 μm) and shear rate (range 200 to 800 s−1) was not different between treatment groups. The number of leukocytes rolling past a defined vessel point was expressed as leukocyte rolling flux, which normalizes for leukocyte count and flow rate. The number of firmly adherent leukocytes (stationary for 30 s) was normalized for the area of vessel wall analyzed. The number of extravasated leukocytes was normalized for the area of tissue analyzed. Results: AT treatment decreased leukocyte rolling flux (23 vs. 15%, P=0.01) induced by an injection of lipopolysaccharide (LPS at 1 μg i.p.) 2 h before observation. However, in this model, AT did not inhibit the number of firmly adherent leukocytes. When mice were pretreated with FOND (0.1 μg/g), the leukocyte rolling flux was increased compared to without heparanoid (22 vs. 25%, P
Print ISSN:
0006-4971
Digitale ISSN:
1528-0020
Thema:
Biologie
,
Medizin
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