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

Nicholas G Jendzjowsky,Nicole O Barioni,Arijit Roy,Margaret M Kelly,Richard L Pye,Francis H Y Green,Richard J A Wilson,Luana Tenorio-Lopes,Christopher N Wyatt

doi:10.1038/s41467-018-06189-y

Nicholas G Jendzjowsky, Nicole O Barioni + Show 7 more

Open Access

https://doi.org/10.1038/s41467-018-06189-y

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Abstract

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.

Highlights

Asthma accounts for 380,000 deaths a year
We demonstrated that TRPV1 receptors are expressed in the terminals of petrosal neurons that innervate the carotid body but lysophosphatidic acid (LPA) binds to 6 LPA-specific G-protein coupled receptors (GPCR), LPAr 1 through 6
We found no evidence for expression of LPAr 2 in these carotid body associated tissues (Fig. 1a, Supplementary Fig. 1a)

Summary

Introduction

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. The effects of allergens/bradykinin on asthmatic lungs is not the release of local inflammatory mediators activating strictly local reflexes[4,5,6,7,8,9,10,11,12,13] but likely involves a circuit that includes the brainstem because vagotomy annuls allergen-induced bronchoconstriction in animal models[12,14] This circuit may be the lung-vagal afferent to parasympathetic efferent reflex pathway that mediates the effects of irritants in naive lungs[11,12,14] or, as carotid body activation elicits bronchoconstriction, the afferent arm of this reflex may originate at the carotid body[15,16,17,18,19,20,21,22,23]. We suggest TRPV1 and LPA receptor blockade may provide a systemic alternative to conventional inhaler-based therapy for acute allergen-induced bronchoconstriction that does not require drug access through compromised airways

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