Increased β2‐adrenoceptor phosphorylation in airway smooth muscle in severe asthma: possible role of mast cell‐derived growth factors

• Published in: Clinical and experimental immunology 2018-11, Vol.194 (2), p.253-258
• Main Authors: Chachi, L., Alzahrani, A., Koziol‐White, C., Biddle, M., Bagadood, R., Panettieri, R. A., Bradding, P., Amrani, Y.
• Format: Article
• Language: English
• Subjects: Adrenergic receptors; Albuterol - pharmacology; allergy; Asthma; Asthma - metabolism; Bronchodilator Agents - pharmacology; Cells, Cultured; Cyclic AMP; Cyclic AMP - metabolism; Disease Progression; Fibroblast Growth Factor 2 - metabolism; Growth factors; Humans; Immunoglobulin E; inflammation; Intercellular Signaling Peptides and Proteins - metabolism; Isoproterenol; Isoproterenol - pharmacology; Lung - drug effects; Lung - physiology; Lungs; Mast cells; Mast Cells - metabolism; Muscles; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Neutralization; Original; Phosphorylation; Protein arrays; Receptors, Adrenergic, beta-2 - metabolism; Receptors, IgE - metabolism; Respiratory System - pathology; Respiratory tract; signal transduction; Smooth muscle; Transforming growth factor; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Tyrosine
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/cei.13191

Summary The purpose of this study was to investigate whether growth factors produced by activated human lung mast cells (HLMCs) impair β2‐adrenoceptor (β2‐AR) function in human airway smooth muscle (ASM) cells. Protein array analysis confirmed the presence of various growth factors, including transforming growth factor (TGF)‐β1, in the supernatants of high‐affinity IgE receptor (FcεRI)‐activated HLMCs which, when applied to ASM cells, impaired albuterol‐induced cyclic adenosine monophosphate (cAMP) production, an effect that was prevented following neutralization of TGF‐β1. This blunted β2‐AR response was reproduced by treating ASM cells with TGF‐β1 or fibroblast growth factor (FGF)‐2, which induced β2‐AR phosphorylation at tyrosine residues Tyr141 and Tyr350, and significantly reduced the maximal bronchorelaxant responses to isoproterenol in human precision cut lung slices (PCLS). Finally, ASM cells isolated from severe asthmatics displayed constitutive elevated β2‐AR phosphorylation at both Tyr141 and Tyr350 and a reduced relaxant response to albuterol. This study shows for the first time that abnormal β2‐AR phosphorylation/function in ASM cells that is induced rapidly by HLMC‐derived growth factors, is present constitutively in cells from severe asthmatics. Despite their clinical benefits, the use of β2 agonists in asthma has been associated with loss of β2‐adrenoceptor function, deleterious effects and/or worsening of the symptoms and asthma deaths. The present study provided the first evidence that abnormal β2‐adrenoceptor phosphorylation/function in airway smooth muscle can be experimentally induced by growth factors released from activated mast cells, a feature that was constitutively present in airway smooth muscle cells from severe asthmatics.