The vagal ganglia transcriptome identifies candidate therapeutics for airway hyperreactivity.

Leah R Reznikov,Margaret Price,Michael J Welsh,Thomas B Bair,Shin-Ping Kuan,David A Stoltz,Mahmoud Abou Alaiwa,Nicholas L Bormann,Yan-Shin J Liao,David K Meyerholz

doi:10.1152/ajplung.00557.2017

Abstract

Mainstay therapeutics are ineffective in some people with asthma, suggesting a need for additional agents. In the current study, we used vagal ganglia transcriptome profiling and connectivity mapping to identify compounds beneficial for alleviating airway hyperreactivity (AHR). As a comparison, we also used previously published transcriptome data from sensitized mouse lungs and human asthmatic endobronchial biopsies. All transcriptomes revealed agents beneficial for mitigating AHR; however, only the vagal ganglia transcriptome identified agents used clinically to treat asthma (flunisolide, isoetarine). We also tested one compound identified by vagal ganglia transcriptome profiling that had not previously been linked to asthma and found that it had bronchodilator effects in both mouse and pig airways. These data suggest that transcriptome profiling of the vagal ganglia might be a novel strategy to identify potential asthma therapeutics.

Highlights

Asthma is a chronic airway disease characterized by wheezing, chest tightness, cough, and variable airflow obstruction [31]
In our previous work [66], we found that loss of acid-sensing ion channel (ASIC) 1a, a proton-gated neuronal cation channel expressed in the vagal ganglia and other neural compartments, prevented airway hyperreactivity (AHR) without decreasing airway inflammation
We found that OVA sensitization increased 492 transcripts and decreased 151 transcripts in the vagal ganglia of WT mice compared with nonsensitized WT mice (Fig. 1A and Supplemental Table S1)

Summary

Introduction

Asthma is a chronic airway disease characterized by wheezing, chest tightness, cough, and variable airflow obstruction [31]. Therapeutics that directly target inflammation, such as glucocorticoids, are not effective in all people with asthma [65]. One attractive candidate is the nervous system and the vagus nerve. As early as the 17th century, anticholinergics, which prevent the postsynaptic actions of acetylcholine released from the vagus nerve, were explored as therapeutics for asthma [64]. Tränkner and colleagues [91] found that ablation of vagal sensory neurons expressing the transient receptor potential vanilloid 1, prevented AHR in ovalbumin (OVA)-sensitized mice without decreasing airway inflammation. In our previous work [66], we found that loss of acid-sensing ion channel (ASIC) 1a, a proton-gated neuronal cation channel expressed in the vagal ganglia and other neural compartments, prevented AHR without decreasing airway inflammation

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