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Long-acting b2 adrenergic agonists (LABAs) provoke Th17-biased asthma


Asthma is a heterogeneous disease with distinct features of airway hyper-responsiveness (AHR) and mucus secretion. In general, long-acting b2 adrenergic agonists (LABAs) are commonly recommended for asthma patients to reduce these symptoms. When LABAs act on airway smooth muscle (ASM), they bind to ASM’s b2 adrenergic receptors (b2ARs) to increase cAMP, which induces bronchodilation effect to ameliorate the AHR. In our previous study, we observed that the G protein-coupled receptors (GPCRs) in dendritic cells (DCs) triggers the Th17 differentiation of naïve T lymphocytes via cAMP signaling. Such a pro-Th17 activity is a serious response because it induces neutrophilic asthma with more severe inflammation. Thus, LABAs, which directly target b2AR of both ASM and lung DCs, need re-evaluation for their risk of causing severe inflammation. Therefore, we examined whether LABAs trigger b2AR of lung DCs and activate Th17 differentiation in asthma. Our results demonstrated that LABA treatment induced Th17 response in both murine DCs and human DC-like cell lines in vitro. Also, we observed that LABA inhalation triggered neutrophilic asthma in vivo. After we had confirmed the side-effect of LABAs, we further examined the combination of LABAs with Inhaled corticosteroids (ICS). Our results from LABA-ICS combination administration showed that the LABA-ICS combination inhibited both Th2 and Th17 response in asthma, supporting the anti-inflammatory effect of ICS with LABAs. Conclusively, we showed that LABAs have a side-effect of inducing neutrophilic asthma with its Th17 response, which suggests that the continuing use of LABAs may worsen the asthmatic symptoms of LABAs users.

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