Format

Send to

Choose Destination
Am J Physiol Lung Cell Mol Physiol. 2015 Nov 15;309(10):L1219-28. doi: 10.1152/ajplung.00156.2015. Epub 2015 Sep 18.

Rosiglitazone elicits in vitro relaxation in airways and precision cut lung slices from a mouse model of chronic allergic airways disease.

Author information

1
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;
2
Faculty of Veterinary Science, University of Melbourne, Parkville, Australia; and.
3
Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia;
4
Department of Allergy and Immunology, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia.
5
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.
6
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.

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.

KEYWORDS:

allergic airways disease; bronchodilation; lung slice; peroxisome proliferator-activated receptor-γ; rosiglitazone

PMID:
26386117
DOI:
10.1152/ajplung.00156.2015
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center