title: Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo.
abstract: Activated mast cells trigger edema in allergic and inflammatory disease. We report a paracrine mechanism by which mast cell-released heparin increases vascular permeability in vivo. Heparin activated the protease factor XII, which initiates bradykinin formation in plasma. Targeting factor XII or kinin B2 receptors abolished heparin-triggered leukocyte-endothelium adhesion and interfered with a mast cell-driven drop in blood pressure in rodents. Intravital laser scanning microscopy and tracer measurements showed heparin-driven fluid extravasation in mouse skin microvessels. Ablation of factor XII or kinin B2 receptors abolished heparin-induced skin edema and protected mice from allergen-activated mast cell-driven leakage. In contrast, heparin and activated mast cells induced excessive edema in mice deficient in the major inhibitor of factor XII, C1 esterase inhibitor. Allergen exposure triggered edema attacks in hereditary angioedema patients, lacking C1 esterase inhibitor. The data indicate that heparin-initiated bradykinin formation plays a fundamental role in mast cell-mediated diseases.
authors.affiliation: Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Chris
authors.initials: C
authors.lastname: Oschatz
authors.forename: Coen
authors.initials: C
authors.lastname: Maas
authors.forename: Bernd
authors.initials: B
authors.lastname: Lecher
authors.forename: Thomas
authors.initials: T
authors.lastname: Jansen
authors.forename: Jenny
authors.initials: J
authors.lastname: Björkqvist
authors.forename: Thomas
authors.initials: T
authors.lastname: Tradler
authors.forename: Reinhard
authors.initials: R
authors.lastname: Sedlmeier
authors.forename: Peter
authors.initials: P
authors.lastname: Burfeind
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Sven
authors.initials: S
authors.lastname: Hammerschmidt
authors.forename: Werner
authors.initials: W
authors.lastname: Müller-Esterl
authors.forename: Walter A
authors.initials: WA
authors.lastname: Wuillemin
authors.forename: Gunnar
authors.initials: G
authors.lastname: Nilsson
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000096:biosynthesis* / Q000235:genetics; D019559:Capillary Leak Syndrome / Q000209:etiology / Q000503:physiopathology*; D002199:Capillary Permeability / Q000502:physiology*; D002448:Cell Adhesion; D050718:Complement C1 Inhibitor Protein / Q000502:physiology; D004487:Edema / Q000209:etiology / Q000503:physiopathology; D042783:Endothelial Cells / Q000473:pathology; D004789:Enzyme Activation; D005174:Factor XII / Q000502:physiology; D006493:Heparin / Q000378:metabolism / Q000502:physiology*; D007022:Hypotension / Q000209:etiology / Q000503:physiopathology; D007073:Immunoglobulin E / Q000276:immunology; D016234:Kallikrein-Kinin System / Q000502:physiology; D007962:Leukocytes / Q000502:physiology; D008297:Male; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D019899:Paracrine Communication / Q000502:physiology; D010323:Passive Cutaneous Anaphylaxis / Q000502:physiology*; D010949:Plasma; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000098:blood supply
chemical_list: D050718:Complement C1 Inhibitor Protein; C487284:Serping1 protein, mouse; D007073:Immunoglobulin E; D005174:Factor XII; D006493:Heparin; D001920:Bradykinin