| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Hatchwell, Luke Girkin, Jason Dun, Matthew D. Morten, Matthew Verrills, Nicole Toop, Hamish D. Morris, Jonathan C. Johnston, Sebastian L. Foster, Paul S. Collison, Adam Mattes, Joerg |
| Description |
Country affiliation: Australia Author Affiliation: Hatchwell L ( Experimental & Translational Respiratory Medicine Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia); Girkin J ( Experimental & Translational Respiratory Medicine Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia); Dun MD ( Medical Biochemistry Department, School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia); Morten M ( Experimental & Translational Respiratory Medicine Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia); Verrills N ( Medical Biochemistry Department, School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia); Toop HD ( School of Chemistry, University of New South Wales, Sydney, Australia.); Morris JC ( School of Chemistry, University of New South Wales, Sydney, Australia.); Johnston SL ( Airway Disease Infection Section, National Heart and Lung Institute, Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom.); Foster PS ( Priority Research Centre for Asthma and Respiratory Diseases, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia.); Collison A ( Experimental & Translational Respiratory Medicine Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia); Mattes J ( Experimental & Translational Respiratory Medicine Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia) |
| Abstract |
BACKGROUND: ß-Agonists are used for relief and control of asthma symptoms by reversing bronchoconstriction. They might also have anti-inflammatory properties, but the underpinning mechanisms remain poorly understood. Recently, a direct interaction between formoterol and protein phosphatase 2A (PP2A) has been described in vitro. OBJECTIVE: We sought to elucidate the molecular mechanisms by which ß-agonists exert anti-inflammatory effects in allergen-driven and rhinovirus 1B-exacerbated allergic airways disease (AAD). METHODS: Mice were sensitized and then challenged with house dust mite to induce AAD while receiving treatment with salmeterol, formoterol, or salbutamol. Mice were also infected with rhinovirus 1B to exacerbate lung inflammation and therapeutically administered salmeterol, dexamethasone, or the PP2A-activating drug (S)-2-amino-4-(4-[heptyloxy]phenyl)-2-methylbutan-1-ol (AAL[S]). RESULTS: Systemic or intranasal administration of salmeterol protected against the development of allergen- and rhinovirus-induced airway hyperreactivity and decreased eosinophil recruitment to the lungs as effectively as dexamethasone. Formoterol and salbutamol also showed anti-inflammatory properties. Salmeterol, but not dexamethasone, increased PP2A activity, which reduced CCL11, CCL20, and CXCL2 expression and reduced levels of phosphorylated extracellular signal-regulated kinase 1 and active nuclear factor κB subunits in the lungs. The anti-inflammatory effect of salmeterol was blocked by targeting the catalytic subunit of PP2A with small RNA interference. Conversely, increasing PP2A activity with AAL(S) abolished rhinovirus-induced airway hyperreactivity, eosinophil influx, and CCL11, CCL20, and CXCL2 expression. Salmeterol also directly activated immunoprecipitated PP2A in vitro isolated from human airway epithelial cells. CONCLUSIONS: Salmeterol exerts anti-inflammatory effects by increasing PP2A activity in AAD and rhinovirus-induced lung inflammation, which might potentially account for some of its clinical benefits. |
| File Format |
HTM / HTML |
| ISSN |
00916749 |
| e-ISSN |
10976825 |
| Journal |
Journal of Allergy and Clinical Immunology |
| Issue Number |
6 |
| Volume Number |
133 |
| Language |
English |
| Publisher |
Elsevier |
| Publisher Date |
2014-06-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Discipline Immunology Adrenergic Beta-2 Receptor Agonists Pharmacology Albuterol Analogs & Derivatives Chemotaxis Drug Effects Immunology Protein Phosphatase 2 Metabolism Respiratory Hypersensitivity Rhinovirus Administration & Dosage Animals Antigens, Dermatophagoides Adverse Effects Disease Models, Animal Enzyme Activation Eosinophils Inflammation Drug Therapy Virology Mice Neutrophils Picornaviridae Infections Salmeterol Xinafoate Research Support, Non-u.s. Gov't |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Immunology and Allergy Immunology |
