腺苷酸环化酶
支气管扩张
受体
呼吸系统
环磷酸腺苷
兴奋剂
内分泌学
气道
内科学
病毒
免疫学
生物
医学
哮喘
支气管扩张剂
麻醉
作者
Terri J. Harford,Fariba Rezaee,Manveen K. Gupta,Vladimir Bokun,Sathyamangla V Naga Prasad,Giovanni Piedimonte
出处
期刊:Science Signaling
[American Association for the Advancement of Science (AAAS)]
日期:2021-06-01
卷期号:14 (685)
被引量:10
标识
DOI:10.1126/scisignal.abc1983
摘要
Pharmacologic agonism of the β2-adrenergic receptor (β2AR) induces bronchodilation by activating the enzyme adenylyl cyclase to generate cyclic adenosine monophosphate (cAMP). β2AR agonists are generally the most effective strategy to relieve acute airway obstruction in asthmatic patients, but they are much less effective when airway obstruction in young patients is triggered by infection with respiratory syncytial virus (RSV). Here, we investigated the effects of RSV infection on the abundance and function of β2AR in primary human airway smooth muscle cells (HASMCs) derived from pediatric lung tissue. We showed that RSV infection of HASMCs resulted in proteolytic cleavage of β2AR mediated by the proteasome. RSV infection also resulted in β2AR ligand-independent activation of adenylyl cyclase, leading to reduced cAMP synthesis compared to that in uninfected control cells. Last, RSV infection caused stronger airway smooth muscle cell contraction in vitro due to increased cytosolic Ca2+ concentrations. Thus, our results suggest that RSV infection simultaneously induces loss of functional β2ARs and activation of multiple pathways favoring airway obstruction in young patients, with the net effect of counteracting β2AR agonist-induced bronchodilation. These findings not only provide a potential mechanism for the reported lack of clinical efficacy of β2AR agonists for treating virus-induced wheezing but also open the path to developing more precise therapeutic strategies.
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