Thrombin and leukocyte recruitment in endotoxemia.
Because thrombin has been implicated in sepsis, it has been proposed that antithrombin III (AT III) is beneficial due to its anticoagulatory and antiadhesive effects. Using intravital microscopy, we visualized leukocyte-endothelium interactions in postcapillary venules of the feline mesentery exposed to lipopolysaccharide (LPS). At a concentration of AT III that blocks leukocyte adhesion in postischemic mesentery, we found no role for thrombin in LPS-induced rolling, adhesion and emigration, or microvascular dysfunction. Furthermore, AT III did not attenuate leukocyte-endothelial interactions after tumor necrosis factor-alpha superfusion of the mesentery. In contrast, fucoidan, a selectin inhibitor, prevented almost all LPS-induced rolling and reduced adhesion, emigration, and microvascular dysfunction. In a model of endotoxemia, leukocyte recruitment into mesentery or lungs was unaffected by AT III. Finally, in a human cell system that mimics the flow conditions in vivo, human neutrophils rolled, adhered, and emigrated similar to the feline postcapillary microvessels, and AT III had no effect on leukocyte recruitment induced by LPS. If AT III has beneficial effects in endotoxemia, it is not due to a direct effect upon leukocyte rolling, adhesion, or emigration in postcapillary venules in vivo.
Woodman
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Department of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1. woodman@ucalgary.ca
Teoh
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Payne
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Kubes
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D000818:Animals; D000990:Antithrombin III / Q000378:metabolism / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology; D002415:Cats; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D015194:Diffusion Chambers, Culture; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D008070:Lipopolysaccharides; D008208:Lymphatic System / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008643:Mesentery / Q000098:blood supply / Q000187:drug effects; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D019087:Selectins / Q000378:metabolism; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D008070:Lipopolysaccharides; D019087:Selectins; D014409:Tumor Necrosis Factor-alpha; D000990:Antithrombin III; D013917:Thrombin