title: Concomitant inhibition of primary equine bronchial fibroblast proliferation and differentiation by selective β2-adrenoceptor agonists and dexamethasone.
abstract: Altered airway cell proliferation plays an important role in the pathogenesis of human bronchial asthma and chronic obstructive pulmonary disease (COPD) as well as the equine recurrent airway obstruction (RAO) with consistent changes, i.e. narrowing the airway wall, explained by proliferation and differentiation of fibroblasts. In permanent cell lines, it has been suggested that β2-adrenoceptor agonists and glucocorticoids regulate cell proliferation via the β2-adrenoceptor pathway; indeed, no study was carried out in fresh isolated primary equine bronchial fibroblasts (EBF). We characterized the β-adrenoceptors in EBF, and compared effects of long-acting (clenbuterol) and short-acting (salbutamol and isoproterenol) β2-agonists and dexamethasone on proliferation, differentiation and collagen synthesis. High density (Bmax; 5037±494 sites/cell) of β2-adrenoceptor subtype was expressed in EBF. β2-agonists inhibited concentration-dependently EBF proliferation with potency of clenbuterol>salbutamol »isoproterenol which was inhibited by ICI 118.551 and propranolol but not by CGP 20712A. In contrast, dexamethasone alone inhibited less EBF proliferation, but the effect was high when dexamethasone was combined with β2-agonists. Transforming growth factor-β1 (TGF-β1) increased transformation of fibroblasts into myofibroblasts, which was inhibited by clenbuterol and dexamethasone alone and drug combination resulted in high inhibition rate. Collagen synthesis in EBF was rather hampered by dexamethasone than by β-agonists. Collectively, the expression of β2-adrenoceptor subtype in EBF and the anti-proliferative effect of clenbuterol suggest that β2-adrenoceptors are growth inhibitory and anti-fibrotic in EBF. These β2-agonist effects in EBF were synergistically enhanced by dexamethasone, providing the additive effects of glucocorticoids to counteract airway remodelling and morbidity of asthma and RAO.
authors.affiliation: Institute of Pharmacology, Pharmacy and Toxicology, University of Leipzig, An den Tierkliniken 15, 04103 Leipzig, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Franke
authors.affiliation: Institute of Pharmacology, Pharmacy and Toxicology, University of Leipzig, An den Tierkliniken 15, 04103 Leipzig, Germany. Electronic address: gabraham@rz.uni-leipzig.de.
authors.forename: Getu
authors.initials: G
authors.lastname: Abraham
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage*; D000402:Airway Obstruction / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D006736:Horses
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D003907:Dexamethasone
keywords: Clenbuterol (PubChem SID: 24892782); Differentiation; Equine; Primary bronchial fibroblasts; Proliferation; β(2)-agonists