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

摘要

Rosiglitazone (RGZ), a per-oxisome proliferator-activated receptor-gamma (PPARgamma) ligand, is a novel dilator of small airways in mouse precision cut lung slices (PCLS). In this study, relaxation to RGZ and beta-adrenoceptor agonists were compared in trachea from naive 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 PPARgamma ligands [RGZ, ciglitazone (CGZ), or 15-deoxy-~(Δ12,14)-prosta-glandin J_2 (15-deoxy-PGJ_2)] or beta-adrenoceptor agonists (isoprenaline and salbutamol). The effects of T0070907 and GW9662 (PPARgamma 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 beta-adrenoceptor agonists in mouse airways but not guinea pig trachea, while 15-deoxy-PGJ_2 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 beta-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 PPARgamma-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 beta-adrenoceptor agonists is limited.