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.

Histone Deacetylase 3 Mediates Allergic Skin Inflammation by Regulating Expression of MCP1 Protein

“…Allergic inflammation, such as PCA, involves vascular permeability resulting from cellular interaction (8). We show that a BALB/c mouse model of PCA involves enhanced vascular permeability and is accompanied by induction of HDAC3 and MCP1 (Fig.…”

“…This suggests a close relationship between PCA and angiogenesis. Mast cells increase vascular permeability by heparin-initiated bradykinin formation (8). Heparin induces anaphylaxis (9).…”

Serglycin: A Structural and Functional Chameleon with Wide Impact on Immune Cells

“…These findings support the earlier reported ability of serglycinlike proteoglycans to inhibit complement activation (62). Finally, a recent study indicates that serglycin (heparin) released from MCs into the circulation may have proinflammatory properties mediated via activation of bradykinin (63).…”

Mast cells as rapid innate sensors of cytomegalovirus by TLR3/TRIF signaling-dependent and -independent mechanisms

“…[15][16][17][18] A large body of evidence indicates that release of vasoactive factors, including histamine, heparin, and TNF, by activated MCs can rapidly activate endothelial cells, 1 and this facilitate the extravasation of leukocytes, including T cells, to extravascular sites of infection, although increased vascular permeability can also contribute to MC-mediated immunopathology. 19 As a further link to adaptive immunity, infected MCs can directly serve as antigen-presenting cells by presenting peptides on MHC I and MHC II molecules, and uninfected MCs have been shown to be able to cross-present antigens. 20,21 The contribution of MCs to antibacterial immunity has been well documented using strains of MC-deficient mice, 1 whereas in vivo evidence for a role of MCs in the control of viral infections is rather limited, but is an emerging topic.…”