Mast cell activation by fibrinogen-related homologous c-terminal peptides (haptides) modulates systemic blood pressure

• Published in: Journal of allergy and clinical immunology 2010-11, Vol.126 (5), p.1041-1048
• Main Authors: Basheer, Maamoun, MSc, Schwalb, Herzl, PhD, Nesher, Maoz, MSc, Gilon, Dan, MD, Shefler, Irit, PhD, Mekori, Yoseph A., MD, Shapira, Oz M., MD, Gorodetsky, Raphael, PhD
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Animals; Antigens - immunology; Antigens - pharmacology; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Cardiology. Vascular system; Cell Degranulation - drug effects; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Enzymes; Experiments; fibrin; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Haptides; Histamine; Histamine H1 Antagonists - pharmacology; Humans; hypotension; Immunopathology; Laboratory animals; Male; mast cells; Mast Cells - drug effects; Mast Cells - immunology; Medical sciences; Peptides; Peptides - immunology; Peptides - pharmacology; Rats; Rats, Sprague-Dawley; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; serotonin
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2010.07.020

Background Haptides are a family of short peptides homologous to C-termini sequences of fibrinogen chains β and γ (haptides Cβ and preCγ, respectively) which were previously shown to penetrate and bind cells. Objectives This work investigates the systemic effect of the haptides with possible clinical implications. Methods Intra-arterial monitoring in rats recorded the haptides' effects on systemic blood pressure. In parallel, their effect was also tested in vitro on isolated rat peritoneal mast cells and on human mast cells. Results Intra-arterial monitoring in rats showed that intravenous administration of low haptides concentrations (35-560 μg/kg rat) caused a shocklike behavior with transient decrease in the systolic and diastolic blood pressure by up to 55% ( P  < .05) in a dose-dependent manner and a minor increase in their heart rate. Randomly scrambled sequences of the haptides had no such effect, suggesting a specific interaction with receptors. Intravenous administration of blockers to histamine receptors H1 and H2 before haptides administration attenuated this effect. Furthermore, in vitro incubation of human LAD2 mast cell line or isolated rat peritoneal mast cells with the haptides caused degranulation of the mast cells. We found that the haptides Cβ and preCγ activated mast cells causing histamine release, resulting in a steep decrease in blood pressure, comparable to anaphylactic shock. Conclusion In treating vascular occlusive diseases, massive fibrinolysis is induced, and haptide-containing sequences are released. We suggest that treatment with histamine receptor blockers or with mast cell stabilizing agents in such pathological conditions may overcome this effect.