期刊
PLOS ONE
卷 10, 期 11, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0142212
关键词
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资金
- American Asthma Foundation [11-0360]
- Clayton Foundation for Research [Corr2012]
- Cancer Center Support Grant [P30 CA16672-38]
- Intramural Research Program of the United States National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIH, NIAID)
Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (beta 2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related beta 2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related beta 2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6.
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