Long-Acting Beta Agonists Enhance Allergic Airway Disease

John M. Knight, Ph.D., Garbo Mak, Joanne Shaw, Catherine McDermott, Luz Roberts, Ran You, Xiaoyi Yuan, Valentine O. Millien, Yuping Qian, Li-Zhen Song, Vincent Frazier, Choel Kim, Jeong j Kim, Richard Bond, Amber U. Luong, MD PhD, Farrah Kheradmand, MD, John McMurray, Pijus K. Mandal, Pietro Morlacchi, Joshua D. Milner, MD, David B. Corry, MD

Abstract: 

Rationale

Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (b2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. We hypothesized that LABAs such as salmeterol and structurally related b2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like disease.

 

Methods

A murine model of fungal-induced allergic lung disease was used to evaluate the potential of β2-AR agonists to promote disease in wild-type and signaling deficient mice. The impact of chronic β2-AR therapy on human cells was also evaluated for relevant markers of disease.

 

Results

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 and that salmeterol-dependent exaggerated allergic disease is due to biased signaling through a pathway involving the b2-AR and beta arrestin 2 (barr2). 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.

 

Conclusions

Structurally related b2-AR ligands aberrantly potentiate STAT6 activation to promote allergic airway disease. This novel and untoward pharmacological property likely explains adverse outcomes observed with LABAs and may be overcome by agents that antagonize STAT6.

abstract No: 

L2
    • AAAAI 2015 (71st)