Journal Article

PreJuSER-14640

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo.

Oschatz, C. ; Maas, C. ; Lecher, B. ; Jansen, T. ; Björkqvist, J. ; Tradler, T. ; Sedlmeier, R. ; Burfeind, P. ; Cichon, S.FZJ* ; Hammerschmidt, S. ; Müller-Esterl, W. ; Wuillemin, W. A. ; Nilsson, G. ; Renné, T.

2011
Cell Press [Cambridge, Mass.]

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Please use a persistent id in citations: doi:10.1016/j.immuni.2011.02.008

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.

Keyword(s): Animals (MeSH) ; Bradykinin: biosynthesis (MeSH) ; Bradykinin: genetics (MeSH) ; Capillary Leak Syndrome: etiology (MeSH) ; Capillary Leak Syndrome: physiopathology (MeSH) ; Capillary Permeability: physiology (MeSH) ; Cell Adhesion (MeSH) ; Complement C1 Inhibitor Protein: physiology (MeSH) ; Edema: etiology (MeSH) ; Edema: physiopathology (MeSH) ; Endothelial Cells: pathology (MeSH) ; Enzyme Activation (MeSH) ; Factor XII: physiology (MeSH) ; Heparin: physiology (MeSH) ; Heparin: secretion (MeSH) ; Hypotension: etiology (MeSH) ; Hypotension: physiopathology (MeSH) ; Immunoglobulin E: immunology (MeSH) ; Kallikrein-Kinin System: physiology (MeSH) ; Leukocytes: physiology (MeSH) ; Male (MeSH) ; Mast Cells: secretion (MeSH) ; Mice (MeSH) ; Paracrine Communication: physiology (MeSH) ; Passive Cutaneous Anaphylaxis: physiology (MeSH) ; Plasma (MeSH) ; Rats (MeSH) ; Signal Transduction: physiology (MeSH) ; Skin: blood supply (MeSH) ; Complement C1 Inhibitor Protein ; Serping1 protein, mouse ; Immunoglobulin E ; Bradykinin ; Factor XII ; Heparin ; J

Note: This work was supported in part by grants from Vetenskapsradet (K2010-64X-21462-01-3), Hjart Lungfonden (20090642), Stockholms lans landsting (ALF, 20090540), Stiftung fur Pathobiochemie und Molekulare Diagnostik of the DGKL, Cancerfonden (100615), and the Federal Ministry of Education and Research (BMBF)-funded ERARE program to T.R. C.M. is supported by a Rubicon fellowship (825-10-012), provided by the Netherlands Organisation for Scientific Research (NWO). T.J. holds a scholarship of the Margarete Waitz-foundation, Mainz. Part of the work of T.T. was performed at Jerini AG, Berlin. We thank L. Kjellen (Uppsala University, Uppsala, Sweden) for providing Ndst2<SUP>-/-</SUP> mice.

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Contributing Institute(s):

1. Strukturelle und funktionelle Organisation des Gehirns (INM-1)

Research Program(s):

1. Funktion und Dysfunktion des Nervensystems (FUEK409) (FUEK409)
2. 89571 - Connectivity and Activity (POF2-89571) (POF2-89571)

Appears in the scientific report 2011

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