Platelet Polyphosphates Are Proinflammatory and Procoagulant Mediators In Vivo
| Autor: | Stephanie A. Smith, Stefan Schmidbauer, Wolfdieter A. Schenk, Thomas Renné, Henri M. H. Spronk, Nicola J. Mutch, James H. Morrissey, William A. Gahl, Lucie Esterl, Felicitas Müller |
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| Rok vydání: | 2009 |
| Předmět: |
Blood Platelets
HUMDISEASE Bradykinin Coagulation Factor XII Pharmacology Biology General Biochemistry Genetics and Molecular Biology Proinflammatory cytokine chemistry.chemical_compound Mice Plasma Polyphosphates otorhinolaryngologic diseases Animals Humans Platelet Platelet activation neoplasms Kininogen Factor XII Fibrin Biochemistry Genetics and Molecular Biology(all) Receptors Bradykinin Thrombosis Factor XII activation digestive system diseases surgical procedures operative chemistry Hermanski-Pudlak Syndrome Immunology Inflammation Mediators Peptide Hydrolases circulatory and respiratory physiology |
| Zdroj: | Cell. 139(6):1143-1156 |
| ISSN: | 0092-8674 |
| DOI: | 10.1016/j.cell.2009.11.001 |
| Popis: | SummaryPlatelets play a central role in thrombosis, hemostasis, and inflammation. We show that activated platelets release inorganic polyphosphate (polyP), a polymer of 60–100 phosphate residues that directly bound to and activated the plasma protease factor XII. PolyP-driven factor XII activation triggered release of the inflammatory mediator bradykinin by plasma kallikrein-mediated kininogen processing. PolyP increased vascular permeability and induced fluid extravasation in skin microvessels of mice. Mice deficient in factor XII or bradykinin receptors were resistant to polyP-induced leakage. PolyP initiated clotting of plasma via the contact pathway. Ablation of intrinsic coagulation pathway proteases factor XII and factor XI protected mice from polyP-triggered lethal pulmonary embolism. Targeting polyP with phosphatases interfered with procoagulant activity of activated platelets and blocked platelet-induced thrombosis in mice. Addition of polyP restored defective plasma clotting of Hermansky-Pudlak Syndrome patients, who lack platelet polyP. The data identify polyP as a new class of mediator having fundamental roles in platelet-driven proinflammatory and procoagulant disorders. |
| Databáze: | OpenAIRE |
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