Long-Acting Beta Agonists Enhance Allergic Airway Disease

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 L...

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Bibliographic Details
Published in:PloS one 2015-11, Vol.10 (11), p.e0142212-e0142212
Main Authors: Knight, John M, Mak, Garbo, Shaw, Joanne, Porter, Paul, McDermott, Catherine, Roberts, Luz, You, Ran, Yuan, Xiaoyi, Millien, Valentine O, Qian, Yuping, Song, Li-Zhen, Frazier, Vincent, Kim, Choel, Kim, Jeong Joo, Bond, Richard A, Milner, Joshua D, Zhang, Yuan, Mandal, Pijus K, Luong, Amber, Kheradmand, Farrah, McMurray, John S, Corry, David B
Format: Article
Language:English
Subjects:
Aberration
Adapter proteins
Adrenergic beta-2 Receptor Agonists - adverse effects
Adrenergic receptors
Agonists (Biochemistry)
Airway management
Albuterol - therapeutic use
Animals
Anti-Asthmatic Agents - adverse effects
Arrestins - deficiency
Arrestins - genetics
Aspergillosis, Allergic Bronchopulmonary - drug therapy
Aspergillosis, Allergic Bronchopulmonary - genetics
Aspergillosis, Allergic Bronchopulmonary - metabolism
Aspergillosis, Allergic Bronchopulmonary - pathology
Aspergillus niger - physiology
Asthma
Asthma - chemically induced
Asthma - drug therapy
Asthma - genetics
Asthma - metabolism
beta-Arrestins
Binding sites
Biochemistry
Bronchoconstriction - drug effects
Carbazoles - adverse effects
Care and treatment
Chronic obstructive lung disease
Complications and side effects
Cytokines
Disease control
Disease Models, Animal
Drugs
FDA approval
Female
Formoterol
Formoterol Fumarate - adverse effects
Gene Expression
Humans
Illnesses
Immunology
Inflammation
Influence
Kinases
Ligands
Lung - drug effects
Lung - metabolism
Lung - pathology
Mice
Mice, Knockout
Mortality
Niger
Peptidomimetics - pharmacology
Pharmacology
Propanolamines - adverse effects
Receptors, Adrenergic, beta-2 - deficiency
Receptors, Adrenergic, beta-2 - genetics
Respiratory tract diseases
Risk factors
Salmeterol
Salmeterol Xinafoate - adverse effects
Signal transduction
Stat6 protein
STAT6 Transcription Factor - agonists
STAT6 Transcription Factor - antagonists & inhibitors
STAT6 Transcription Factor - genetics
STAT6 Transcription Factor - metabolism
Transcription factors
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0142212