Heparin binds to lipopolysaccharide (LPS)-binding protein, facilitates the transfer of LPS to CD14, and enhances LPS-induced activation of peripheral blood monocytes.
Heparin is one of the most effective drugs for preventing and treating thromboembolic complications in surgical patients. Recent evidence suggests that heparin enhances the proinflammatory responses of human peripheral blood monocytes to Gram-negative endotoxin (LPS). We have identified LPS-binding protein (LBP) as a novel heparin-binding plasma protein. The affinity of LPB to heparin was KD = 55 +/- 8 nM, as measured by surface plasmon resonance. Using a fluorescence-based assay, we showed that clinically used heparin preparations significantly enhance the ability of LBP to catalytically disaggregate and transfer LPS to CD14, the LPS receptor. The presence of clinically relevant heparin concentrations in human whole blood increased LPS-induced production of the proinflammatory cytokine IL-8. Fondaparinux, which is identical with the antithrombin III-binding pentasaccharide in heparin, did not bind to LBP or alter LBP function. Thus, this novel anticoagulant drug is a potential candidate for safe administration to patients who have endotoxemia and require anticoagulation.
Heinzelmann
Michael
M
Department of Surgery, University Hospital, Zurich, Switzerland. mheinzelmann@bluewin.ch
Bosshart
Herbert
H
D000209:Acute-Phase Proteins / Q000378:metabolism*; D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D000990:Antithrombin III / Q000378:metabolism; D001692:Biological Transport / Q000276:immunology; D001896:Boron Compounds; D002352:Carrier Proteins / Q000378:metabolism*; D017984:Enoxaparin / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000737:chemistry; D006493:Heparin / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D012995:Solubility; D013431:Sulfates / Q000737:chemistry; D013682:Teichoic Acids / Q000737:chemistry; D013917:Thrombin / Q000378:metabolism; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D000276:Adjuvants, Immunologic; D000990:Antithrombin III; D001896:Boron Compounds; D002352:Carrier Proteins; D017984:Enoxaparin; D005456:Fluorescent Dyes; D006493:Heparin; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D013431:Sulfates; D013682:Teichoic Acids; D013917:Thrombin; D000099231:Lipopolysaccharide-Binding Protein; C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; C009900:lipoteichoic acid