Abstract
An acidic microenvironment has been shown to evoke a variety of airway responses, including cough, bronchoconstriction, airway hyperresponsiveness (AHR), infiltration of inflammatory cells in the lung, and stimulation of mucus hyperproduction. Except for the participation of transient receptor potential vanilloid-1 (TRPV1) and acid-sensing ion channels (ASICs) in severe acidic pH (of less than 6.0)-induced cough and bronchoconstriction through sensory neurons, the molecular mechanisms underlying extracellular acidic pH-induced actions in the airways have not been fully understood. Recent studies have revealed that ovarian cancer G protein-coupled receptor 1 (OGR1)-family G protein-coupled receptors, which sense pH of more than 6.0, are expressed in structural cells, such as airway smooth muscle cells and epithelial cells, and in inflammatory and immune cells, such as eosinophils and dendritic cells. They function in a variety of airway responses related to the pathophysiology of inflammatory diseases, including allergic asthma. In the present review, we discuss the roles of ionotropic TRPV1 and ASICs and metabotropic OGR1-family G protein-coupled receptors in the airway inflammation and AHR in asthma and respiratory diseases.
Highlights
Airway acidification has been shown to be attained by either the exogenous way, that is, the microaspiration of acid contents into the airway during gastroesophageal reflux and inhalation of low pH pollutant aerosol, or the endogenous way, that is, ischemia and inflammation of the airways in inflammatory diseases, such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD) [1,2,3]
In addition to transient receptor potential vanilloid-1 (TRPV1), involvement of acid-sensing ion channels (ASICs) in acidic pH-induced airway hyperreactivity (AHR) was suggested by using selective ASIC inhibitors in the guinea pig tracheal rings ex vivo [28]. These results suggest that bronchoconstriction and AHR under acidic environments are indirectly mediated by sensory neurons through proton-sensing channels, such as TRPV1 and ASICs [6, 30]
The same group has shown that TRPV1 is expressed and citric acid-induced mucin secretion is mediated by Ca2+ influx via TRPV1 in the same cells [41]. These results suggest that epithelial cells utilize different proton-sensing machineries depending on the acidity of microenvironments; ovarian cancer G protein-coupled receptor 1 (OGR1)-family G proteincoupled receptors (GPCRs) sense mild alkaline to acidic pH of 8 to 6, whereas TRPV1 senses more acidic pH of 6 to 4, as described above
Summary
Airway acidification has been shown to be attained by either the exogenous way, that is, the microaspiration of acid contents into the airway during gastroesophageal reflux and inhalation of low pH pollutant aerosol, or the endogenous way, that is, ischemia and inflammation of the airways in inflammatory diseases, such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD) [1,2,3]. Exposure to acids evokes a cough, bronchoconstriction, airway hyperreactivity (AHR), and microvascular leakage and stimulates mucus production [2]. Molecular mechanisms underlying the extracellular acidic pH-induced actions in the airways have not been fully understood. We discuss the proton-sensing mechanisms, focusing on proton-sensing ionotropic receptors, such as transient receptor potential vanilloid-1 (TRPV1) and acidsensing ion channels (ASICs), and metabotropic ovarian cancer G protein-coupled receptor 1 (OGR1)-family G proteincoupled receptors (GPCRs), in the airway inflammation and AHR in asthma and respiratory diseases
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