PLoS ONE 2015-01-01

Long-Acting Beta Agonists Enhance Allergic Airway Disease.

John M Knight, Garbo Mak, Joanne Shaw, Paul Porter, Catherine McDermott, Luz Roberts, Ran You, Xiaoyi Yuan, Valentine O Millien, Yuping Qian, Li-Zhen Song, Vincent Frazier, Choel Kim, Jeong Joo Kim, Richard A Bond, Joshua D Milner, Yuan Zhang, Pijus K Mandal, Amber Luong, Farrah Kheradmand, John S McMurray, David B Corry

Index: PLoS ONE 10 , e0142212, (2015)

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Abstract

Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-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 β2-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 β2-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.