Acid-Sensing Ion Channel 1a Contributes to Airway Hyperreactivity in Mice.

Leah R Reznikov,David K Meyerholz,David A Stoltz,Michael J Welsh,Margaret P Price,Ryan J Adam,Omar Jaffer,Linda S Powers,Andrew S Michalski,Mahmoud Abou Alaiwa,Agustín Guerrero-Hernandez

doi:10.1371/journal.pone.0166089

Abstract

Neurons innervating the airways contribute to airway hyperreactivity (AHR), a hallmark feature of asthma. Several observations suggested that acid-sensing ion channels (ASICs), neuronal cation channels activated by protons, might contribute to AHR. For example, ASICs are found in vagal sensory neurons that innervate airways, and asthmatic airways can become acidic. Moreover, airway acidification activates ASIC currents and depolarizes neurons innervating airways. We found ASIC1a protein in vagal ganglia neurons, but not airway epithelium or smooth muscle. We induced AHR by sensitizing mice to ovalbumin and found that ASIC1a-/- mice failed to exhibit AHR despite a robust inflammatory response. Loss of ASIC1a also decreased bronchoalveolar lavage fluid levels of substance P, a sensory neuropeptide secreted from vagal sensory neurons that contributes to AHR. These findings suggest that ASIC1a is an important mediator of AHR and raise the possibility that inhibiting ASIC channels might be beneficial in asthma.

Highlights

Studies over the last few decades indicate that the nervous system is a critical mediator of hallmark features of asthma, including cough, mucus secretion and airway hyperreactivity (AHR) [1,2,3,4,5,6]
Compared to ASIC1a-/- tissue, tissue from wild-type mice showed no specific immunostaining in airway smooth muscle (Fig 1C) or airway epithelia (Fig 1C and 1D), even though immunostaining procedures occurred at the same time and under the same conditions as the vagal ganglia immunostaining
We made numerous attempts to identify ASIC1a immunostaining in nerve endings innervating the airway, but no specific staining was observed

Summary

Introduction

Studies over the last few decades indicate that the nervous system is a critical mediator of hallmark features of asthma, including cough, mucus secretion and airway hyperreactivity (AHR) [1,2,3,4,5,6]. Greater sensory nerve innervation [7] and increased levels of sensory neuropeptides have been observed in asthmatic airways [8, 9]. Persistent AHR in the absence of inflammation is associated with a doubling of airway smooth muscle innervation [10]. Ablation of airway sensory neurons that express the transient receptor potential vanilloid 1 (TRPV1) gene reduces AHR in inflamed airways [11]. Inactivation of sensory neurons expressing Nav1.8 or blockade of Nav1.8 reduces

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Conclusion