OBJECTIVE: To investigate whether the protective effect of antithrombin III, which has been shown to exert beneficial effects during septic disorders, including reduction of endotoxin-associated leukocyte/endothelial cell interaction and capillary perfusion failure, is mainly based on its anticoagulant capacity or direct effects on the microvascular endothelium. DESIGN: Animal study with three treatment groups. SETTING: Animal research facility. SUBJECTS: Syrian golden hamsters, 6-8 wks old with a body weight of 60-80 g. INTERVENTIONS: In skinfold preparations of hamsters, normotensive endotoxemia was induced by intravenous administration of 2 mg/kg endotoxin (lipopolysaccharide, 2 mg/kg). Antithrombin III (n = 7 animals; 250 units/kg) or tryptophan49-blocked antithrombin III (n = 6; 250 units/kg) was substituted intravenously 5 mins before lipopolysaccharide administration. Saline-treated animals (n = 11), receiving only lipopolysaccharide, served as controls. Tryptophan49-blocked antithrombin III binds to glycosaminoglycans at the endothelial surface to a significantly lower extent while retaining its progressive anticoagulant effects. MEASUREMENTS AND MAIN RESULTS: Compared with controls, antithrombin III significantly reduced lipopolysaccharide-induced arteriolar and venular leukocyte adherence (p < .01) and prevented depression of functional capillary density (p < .01), whereas tryptophan49-blocked antithrombin III failed to significantly improve both variables. As measured in vivo by a monoclonal fluorescein isothiocyanate-labeled anti-antithrombin III antibody and intravital microscopy, the lack of effect of tryptophan49-blocked antithrombin III was associated with significantly lower antithrombin III/endothelium binding coefficients after 1 hr, 3 hrs, and 24 hrs of endotoxemia (p < .01). CONCLUSIONS: We conclude that specific antithrombin III interactions with cell-surface glycosaminoglycans on the endothelium rather than anticoagulant properties are the mechanism of antithrombin III-mediated attenuation of leukocyte/endothelial cell interaction and capillary perfusion failure.
OBJECTIVE: To investigate whether the protective effect of antithrombin III, which has been shown to exert beneficial effects during septic disorders, including reduction of endotoxin-associated leukocyte/endothelial cell interaction and capillary perfusion failure, is mainly based on its anticoagulant capacity or direct effects on the microvascular endothelium. DESIGN: Animal study with three treatment groups. SETTING: Animal research facility. SUBJECTS:Syrian golden hamsters, 6-8 wks old with a body weight of 60-80 g. INTERVENTIONS: In skinfold preparations of hamsters, normotensive endotoxemia was induced by intravenous administration of 2 mg/kg endotoxin (lipopolysaccharide, 2 mg/kg). Antithrombin III (n = 7 animals; 250 units/kg) or tryptophan49-blocked antithrombin III (n = 6; 250 units/kg) was substituted intravenously 5 mins before lipopolysaccharide administration. Saline-treated animals (n = 11), receiving only lipopolysaccharide, served as controls. Tryptophan49-blocked antithrombin III binds to glycosaminoglycans at the endothelial surface to a significantly lower extent while retaining its progressive anticoagulant effects. MEASUREMENTS AND MAIN RESULTS: Compared with controls, antithrombin III significantly reduced lipopolysaccharide-induced arteriolar and venular leukocyte adherence (p < .01) and prevented depression of functional capillary density (p < .01), whereas tryptophan49-blocked antithrombin III failed to significantly improve both variables. As measured in vivo by a monoclonal fluorescein isothiocyanate-labeled anti-antithrombin III antibody and intravital microscopy, the lack of effect of tryptophan49-blocked antithrombin III was associated with significantly lower antithrombin III/endothelium binding coefficients after 1 hr, 3 hrs, and 24 hrs of endotoxemia (p < .01). CONCLUSIONS: We conclude that specific antithrombin III interactions with cell-surface glycosaminoglycans on the endothelium rather than anticoagulant properties are the mechanism of antithrombin III-mediated attenuation of leukocyte/endothelial cell interaction and capillary perfusion failure.
Authors: Nicole C Smits; Takashi Kobayashi; Pratyaksh K Srivastava; Sladjana Skopelja; Julianne A Ivy; Dustin J Elwood; Radu V Stan; Gregory J Tsongalis; Frank W Sellke; Peter L Gross; Michael D Cole; James T DeVries; Aaron V Kaplan; John F Robb; Scott M Williams; Nicholas W Shworak Journal: Matrix Biol Date: 2017-01-23 Impact factor: 11.583
Authors: Daniel De Backer; Katia Donadello; Fabio Silvio Taccone; Gustavo Ospina-Tascon; Diamantino Salgado; Jean-Louis Vincent Journal: Ann Intensive Care Date: 2011-07-19 Impact factor: 6.925
Authors: Mohamed ElSaadani; Syed M Ahmed; Christina Jacovides; Alfonso Lopez; Victoria E Johnson; Lewis J Kaplan; C William Schwab; Douglas H Smith; Jose L Pascual Journal: J Trauma Acute Care Surg Date: 2021-02-01 Impact factor: 3.313