Making sense of scents in the lung: Odor transduction in human airway smooth muscle
Embargo until
2022-08-01
Date
2018-07-16
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Publisher
Johns Hopkins University
Abstract
Asthma is a chronic lung disease that affects millions of people worldwide, and is associated with considerable social and economic burdens such as reduced quality of life and increased healthcare costs. One of the main characteristics of asthma is airflow obstruction caused by airway smooth muscle (ASM) cells, the end effectors of airway narrowing. ASM cells from severe asthmatics are hypercontractile, prompting the use of bronchodilator therapy to relax the cells and reopen the airways. However, treatment options aimed to control and prevent bronchoconstriction are limited in number and success, and novel effective treatments that target ASM are still lacking. In an effort to discover new targets in ASM for asthma treatment, we focused on studying the non-traditional role of sensory receptors and their ligands in ASM cells.
Olfactory receptors (ORs) are exquisitely sensitive G protein-coupled chemosensors that mediate the detection of scents in the olfactory epithelium. Here we report that these same chemosensors and their downstream effectors are expressed in human ASM cells, where they modulate ASM biology. Using degenerate PCR and RNA-Seq data, we discovered 62 ORs in human ASM cells. The ligands for one of these ORs, OR51E2, mediate changes in the cell characteristics associated with asthma: cell proliferation, cell stiffness, and cytoskeleton remodeling.
While OR51E2 ligands are volatile fatty acids, the characterization of a viable olfactory system in ASM prompted the hypothesis that other odorants may modulate ASM function. We show that volatile chemicals encompassing a range of scents can directly affect ASM contractility. In this spectrum of odor molecules, monoterpenes that are reported to possess anti-spasmodic and anti-inflammatory properties emerged as a universal ASM relaxant. We show that the effects of a particular monoterpene, nerol, were modulated by an OR (OR2W3). We further demonstrate that nerol-induced [Ca2+]i and ASM relaxation were ablated by chelating extracellular calcium and by pharmacological inhibition of store-operated Ca2+ and ATP-sensitive K+ channels.
Taken together, our results provide first insight into the expression and function of ORs in ASM. These studies established a new chemosensory signal transduction in human ASM cells, and showed that ORs and their ligands may be a novel chemomechanical nodal point to mitigate obstructive lung disease.
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Keywords
olfactory receptors, airway smooth muscle, asthma