G protein-coupled receptors in the neuropathophysiology of asthma Public Deposited

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  • March 20, 2019
Creator
  • Allen, Irving Coy, Jr.
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Asthma is a complex genetic disorder with environmental influences and is characterized by airway inflammation, reversible airflow obstruction, and airway hyperresponsiveness (AHR). The arachidonic acid metabolite thromboxane A2 (TXA2), is a potent lipid mediator released by platelets and inflammatory cells and is capable of inducing bronchoconstriction. In the airways, it has been postulated that TXA2 causes airway constriction by direct activation of TP receptors on airway smooth muscle (ASM) cells. Here we demonstrate that although TXA2 can mediate a dramatic increase in ASM constriction, this response is largely dependent on vagal innervation of the airways and is highly sensitive to muscarinic acetylcholine receptor (mAChR) antagonists. Further analyses demonstrate that TP-dependent ASM constriction requires M3 mAChR expression. To further define the mechanism underlying TXA2 meditated airway constriction, mice carrying a Tp receptor locus that is sensitive to disruption by cre recombinase were generated. These mice were crossed with nestin-cre transgenic mice, which express cre recombinase throughout the nervous systems. Here we demonstrate that loss of the TP receptor throughout the nervous system does not significantly affect TXA2 airway reactivity. To assess ASM TP receptor function, we crossed the floxed Tp receptor mice with SM22-cre transgenic mice, which express cre recombinase in smooth muscle. The resultant smooth muscle TP receptor deficient animals demonstrate attenuated airway responses following aerosol challenges with TXA2. Together, these findings suggest that TXA2 mediates airway reactivity and AHR through collaborations between ASM Tp receptors and the M3 mAChR. In addition to TXA2, we also evaluated the role of NPSR1 (GPRA), a newly deorphanized G protein-coupled receptor that has been shown to be a promising candidate gene associated with asthma in human populations. We report here that the change in airway resistance in response to methacholine was identical in control and NPSR1 deficient mice and the development of allergic lung disease in NPSR1 deficient mice is unaltered. In contrast to previously published data, our analyses also failed to detect expression of NPSR1 in human lung tissue or in mice with allergic lung disease. Taken together, our studies fail to support a direct contribution of NPSR1 to asthma pathogenesis.
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  • In Copyright
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  • Koller, Beverly H.
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