title: Rosiglitazone elicits in vitro relaxation in airways and precision cut lung slices from a mouse model of chronic allergic airways disease.
abstract: Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor-γ (PPARγ) ligand, is a novel dilator of small airways in mouse precision cut lung slices (PCLS). In this study, relaxation to RGZ and β-adrenoceptor agonists were compared in trachea from naïve mice and guinea pigs and trachea and PCLS from a mouse model of chronic allergic airways disease (AAD). Airways were precontracted with methacholine before addition of PPARγ ligands [RGZ, ciglitazone (CGZ), or 15-deoxy-(Δ12,14)-prostaglandin J2 (15-deoxy-PGJ2)] or β-adrenoceptor agonists (isoprenaline and salbutamol). The effects of T0070907 and GW9662 (PPARγ antagonists) or epithelial removal on relaxation were assessed. Changes in force of trachea and lumen area in PCLS were measured using preparations from saline-challenged mice and mice sensitized (days 0 and 14) and challenged with ovalbumin (3 times/wk, 6 wk). RGZ and CGZ elicited complete relaxation with greater efficacy than β-adrenoceptor agonists in mouse airways but not guinea pig trachea, while 15-deoxy-PGJ2 did not mediate bronchodilation. Relaxation to RGZ was not prevented by T0070907 or GW9662 or by epithelial removal. RGZ-induced relaxation was preserved in the trachea and increased in PCLS after ovalbumin-challenge. Although RGZ was less potent than β-adrenoceptor agonists, its effects were additive with salbutamol and isoprenaline and only RGZ maintained potency and full efficacy in maximally contracted airways or after allergen challenge. Acute PPARγ-independent, epithelial-independent airway relaxation to RGZ is resistant to functional antagonism and maintained in both trachea and PCLS from a model of chronic AAD. These novel efficacious actions of RGZ support its therapeutic potential in asthma when responsiveness to β-adrenoceptor agonists is limited.
authors.affiliation: Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia; Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia;
authors.forename: Chantal
authors.initials: C
authors.lastname: Donovan
authors.affiliation: Faculty of Veterinary Science, University of Melbourne, Parkville, Australia; and.
authors.forename: Simon R
authors.initials: SR
authors.lastname: Bailey
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia;
authors.forename: Jenny
authors.initials: J
authors.lastname: Tran
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia;
authors.forename: Gertruud
authors.initials: G
authors.lastname: Haitsma
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia;
authors.forename: Zaridatul A
authors.initials: ZA
authors.lastname: Ibrahim
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia;
authors.forename: Simon R
authors.initials: SR
authors.lastname: Foster
authors.affiliation: Department of Allergy and Immunology, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia.
authors.forename: Mimi L K
authors.initials: ML
authors.lastname: Tang
authors.affiliation: Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia; Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia; Department of Allergy and Immunology, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Royce
authors.affiliation: Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Australia; Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia; jane.bourke@monash.edu.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Bourke
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D004353:Drug Evaluation, Preclinical; D005260:Female; D006168:Guinea Pigs; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects / Q000503:physiopathology
chemical_list: D000318:Adrenergic beta-Agonists; D018927:Anti-Asthmatic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D016210:Methacholine Chloride
keywords: allergic airways disease; bronchodilation; lung slice; peroxisome proliferator-activated receptor-γ; rosiglitazone