title: Long-Acting Beta Agonists Enhance Allergic Airway Disease.
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.
authors.affiliation: Departments of Pathology & Immunology and Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: John M
authors.initials: JM
authors.lastname: Knight
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Garbo
authors.initials: G
authors.lastname: Mak
authors.affiliation: Department of Otorhinolaryngolgy - Head and Neck Surgery, University of Texas Medical School at Houston, Houston, Texas, United States of America.
authors.forename: Joanne
authors.initials: J
authors.lastname: Shaw
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Porter
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Catherine
authors.initials: C
authors.lastname: McDermott
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Luz
authors.initials: L
authors.lastname: Roberts
authors.affiliation: Departments of Pathology & Immunology and Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Ran
authors.initials: R
authors.lastname: You
authors.affiliation: Departments of Pathology & Immunology and Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Medicine and the Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Valentine O
authors.initials: VO
authors.lastname: Millien
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: Song
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Vincent
authors.initials: V
authors.lastname: Frazier
authors.affiliation: Departments of Pharmacology, and Biochemistry & Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Choel
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Biochemistry & Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Jeong Joo
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, Texas, United States of America.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bond
authors.affiliation: Laboratory of Allergic Diseases, National Institutes of Allergic and Infectious Disease, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
authors.affiliation: Laboratory of Allergic Diseases, National Institutes of Allergic and Infectious Disease, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Pijus K
authors.initials: PK
authors.lastname: Mandal
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center and the Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Medical School at Houston, Houston, Texas, United States of America.
authors.forename: Amber
authors.initials: A
authors.lastname: Luong
authors.affiliation: Departments of Medicine and Pathology & Immunology, Translational Biology and Molecular Medicine Program, and the Biology of Inflammation Center, Baylor College of Medicine and the Michael E. DeBakey VA Center for Translational Research on Inflammatory Diseases, Houston, Texas, United States of America.
authors.forename: Farrah
authors.initials: F
authors.lastname: Kheradmand
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: John S
authors.initials: JS
authors.lastname: McMurray
authors.affiliation: Departments of Medicine and Pathology & Immunology, Translational Biology and Molecular Medicine Program, and the Biology of Inflammation Center, Baylor College of Medicine and the Michael E. DeBakey VA Center for Translational Research on Inflammatory Diseases, Houston, Texas, United States of America.
authors.forename: David B
authors.initials: DB
authors.lastname: Corry
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000009:adverse effects*; D000420:Albuterol / Q000627:therapeutic use; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000009:adverse effects*; D019390:Arrestins / Q000172:deficiency / Q000235:genetics; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001234:Aspergillus niger / Q000502:physiology; D001249:Asthma / Q000139:chemically induced* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects; D002227:Carbazoles / Q000009:adverse effects; D000077261:Carvedilol; D004195:Disease Models, Animal; D005260:Female; D000068759:Formoterol Fumarate / Q000009:adverse effects; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D057786:Peptidomimetics / Q000494:pharmacology*; D011412:Propanolamines / Q000009:adverse effects; D018343:Receptors, Adrenergic, beta-2 / Q000172:deficiency / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000068299:Salmeterol Xinafoate / Q000009:adverse effects; D000071557:beta-Arrestins
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018927:Anti-Asthmatic Agents; D019390:Arrestins; D002227:Carbazoles; D057786:Peptidomimetics; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D000071557:beta-Arrestins; D000077261:Carvedilol; D000068299:Salmeterol Xinafoate; D000420:Albuterol; D000068759:Formoterol Fumarate