caa a22 4500 445854022 CHVBK 20180317145422.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1007/s00204-010-0564-2 doi (NATIONALLICENCE)springer-10.1007/s00204-010-0564-2 Marine brevetoxin induces IgE-independent mast cell activation [Elektronische Daten] [Susana Hilderbrand, Rachel Murrell, James Gibson, Jared Brown] Brevetoxins (PbTx) are sodium channel neurotoxins produced by the marine dinoflagellate Karenia brevis during red tide blooms. Inhalation of PbTx in normal individuals and individuals with pre-existing airways disease results in adverse airway symptoms including bronchoconstriction. In animal models of allergic inflammation, inhalation of PbTx results in a histamine H1-mediated bronchoconstriction suggestive of mast cell activation. How mast cells would respond directly to PbTx is unknown. We thus explored the activation of mouse bone marrow-derived mast cells (BMMCs) following exposure to purified PbTx-2. Following in vitro exposure to PbTx-2, we examined cellular viability, mast cell degranulation (β-hexosaminidase release), intracellular Ca2+ and Na+ flux, and the production of inflammatory mediators (IL-6). PbTx-2 induced significant cellular toxicity within 24h as measured by LDH release and Annexin-V staining. However, within 1h of exposure, PbTx-2 induced BMMC degranulation and an increase in IL-6 mRNA expression independent of the high-affinity IgE receptor (FcεRI) stimulation. Activation of BMMCs by PbTx-2 was associated with altered intracellular Ca2+ and Na+ levels. Brevenal, a naturally produced compound that antagonizes the activity of PbTx, prevented changes in intracellular Na+ levels but did not alter activation of BMMCs by PbTx-2. These findings demonstrate that PbTx-2 activates mast cells independent of FcεRI providing insight into critical events in the pathogenesis and a potential therapeutic target in brevetoxin-induced airway symptoms. Springer-Verlag, 2010 Brevetoxin nationallicence Mast cell nationallicence Immune nationallicence Hilderbrand Susana Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Medical Sciences Building, 6W-33, 600 Moye Blvd, 27834, Greenville, NC, USA aut Murrell Rachel Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Medical Sciences Building, 6W-33, 600 Moye Blvd, 27834, Greenville, NC, USA aut Gibson James Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Medical Sciences Building, 6W-33, 600 Moye Blvd, 27834, Greenville, NC, USA aut Brown Jared Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Medical Sciences Building, 6W-33, 600 Moye Blvd, 27834, Greenville, NC, USA aut Archives of Toxicology Springer-Verlag 85/2(2011-02-01), 135-141 0340-5761 85:2<135 2011 85 204 https://doi.org/10.1007/s00204-010-0564-2 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00204-010-0564-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Hilderbrand Susana Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Medical Sciences Building, 6W-33, 600 Moye Blvd, 27834, Greenville, NC, USA aut NATIONALLICENCE 700 1- Murrell Rachel Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Medical Sciences Building, 6W-33, 600 Moye Blvd, 27834, Greenville, NC, USA aut NATIONALLICENCE 700 1- Gibson James Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Medical Sciences Building, 6W-33, 600 Moye Blvd, 27834, Greenville, NC, USA aut NATIONALLICENCE 700 1- Brown Jared Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Medical Sciences Building, 6W-33, 600 Moye Blvd, 27834, Greenville, NC, USA aut NATIONALLICENCE 773 0- Archives of Toxicology Springer-Verlag 85/2(2011-02-01), 135-141 0340-5761 85:2<135 2011 85 204 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer