1. Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo.
- Author
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Oschatz C, Maas C, Lecher B, Jansen T, Björkqvist J, Tradler T, Sedlmeier R, Burfeind P, Cichon S, Hammerschmidt S, Müller-Esterl W, Wuillemin WA, Nilsson G, and Renné T
- Subjects
- Animals, Bradykinin genetics, Capillary Leak Syndrome etiology, Cell Adhesion, Complement C1 Inhibitor Protein physiology, Edema etiology, Edema physiopathology, Endothelial Cells pathology, Enzyme Activation, Factor XII physiology, Heparin metabolism, Hypotension etiology, Hypotension physiopathology, Immunoglobulin E immunology, Kallikrein-Kinin System physiology, Leukocytes physiology, Male, Mice, Paracrine Communication physiology, Plasma, Rats, Signal Transduction physiology, Skin blood supply, Bradykinin biosynthesis, Capillary Leak Syndrome physiopathology, Capillary Permeability physiology, Heparin physiology, Mast Cells metabolism, Passive Cutaneous Anaphylaxis physiology
- 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., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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