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Preventing acute asthmatic symptoms by targeting a neuronal mechanism involving carotid body lysophosphatidic acid receptors

Asthma accounts for 380,000 deaths a year. Carotid body denervation has been shown to have a profound effect on airway hyper-responsiveness in animal models but a mechanistic explanation is lacking. Here we demonstrate, using a rat model of asthma (OVA-sensitized), that carotid body activation durin...

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Bibliographic Details
Published in:Nature communications 2018-10, Vol.9 (1), p.4030-15, Article 4030
Main Authors: Jendzjowsky, Nicholas G., Roy, Arijit, Barioni, Nicole O., Kelly, Margaret M., Green, Francis H. Y., Wyatt, Christopher N., Pye, Richard L., Tenorio-Lopes, Luana, Wilson, Richard J. A.
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Language:English
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Summary:Asthma accounts for 380,000 deaths a year. Carotid body denervation has been shown to have a profound effect on airway hyper-responsiveness in animal models but a mechanistic explanation is lacking. Here we demonstrate, using a rat model of asthma (OVA-sensitized), that carotid body activation during airborne allergic provocation is caused by systemic release of lysophosphatidic acid (LPA). Carotid body activation by LPA involves TRPV1 and LPA-specific receptors, and induces parasympathetic (vagal) activity. We demonstrate that this activation is sufficient to cause acute bronchoconstriction. Moreover, we show that prophylactic administration of TRPV1 (AMG9810) and LPA (BrP-LPA) receptor antagonists prevents bradykinin-induced asthmatic bronchoconstriction and, if administered following allergen exposure, reduces the associated respiratory distress. Our discovery provides mechanistic insight into the critical roles of carotid body LPA receptors in allergen-induced respiratory distress and suggests alternate treatment options for asthma. Acute bronchoconstriction is the leading cause of asthmatic sudden death following allergen exposure. The authors show that the systemic increase of LPA following inhaled allergen or bradykinin challenge activates the carotid bodies through TRPV1 and LPA-specific receptors and that systemic TRPV1 and LPA-specific receptor antagonists ameliorate acute bronchoconstriction.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-018-06189-y