Novel small airway bronchodilator responses to rosiglitazone in mouse lung slices

Jane E. Bourke, Yan Bai, Chantal Donovan, James G. Esposito, Xiahui Tan, Michael J. Sanderson

Research output: Contribution to journalArticleResearchpeer-review

20 Citations (Scopus)

Abstract

There is a need to identify novel agents that elicit small airway relaxation when β2-adrenoceptor agonists become ineffective in difficult-to-treat asthma. Because chronic treatment with the synthetic peroxisome proliferator activated receptor (PPAR)γ agonist rosiglitazone (RGZ) inhibits airway hyperresponsiveness in mouse models of allergic airways disease, we tested the hypothesis that RGZ causes acute airway relaxation by measuring changes in small airway size in mouse lung slices. Whereas the β-adrenoceptor agonists albuterol (ALB) and isoproterenol induced partial airway relaxation, RGZ reversed submaximal and maximal contraction to methacholine (MCh) and was similarly effective after precontraction with serotonin or endothelin-1. Concentration-dependent relaxation to RGZ was not altered by the β-adrenoceptor antagonist propranolol and was enhanced by ALB. RGZ-induced relaxation wasmimicked by other synthetic PPARγ agonists but not by the putative endogenous agonist 15-deoxy-PGJ2 and was not prevented by the PPARγ antagonist GW9662. To induce airway relaxation, RGZ inhibited the amplitude and frequency of MCh-induced Ca2+ oscillations of airway smooth muscle cells (ASMCs). In addition, RGZ reduced MCh-induced Ca2+ sensitivity of the ASMCs. Collectively, these findings demonstrate that acute bronchodilator responses induced by RGZ are PPARγ independent, additive with ALB, and occur by the inhibition of ASMC Ca2+ signaling and Ca2+ sensitivity. Because RGZ continues to elicit relaxation when β-adrenoceptor agonists have a limited effect, RGZ or related compounds may have potential as bronchodilators for the treatment of difficult asthma. 

Original languageEnglish
Pages (from-to)748-756
Number of pages9
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume50
Issue number4
DOIs
Publication statusPublished - 1 Apr 2014
Externally publishedYes

Keywords

  • Airway smooth muscle
  • Asthma
  • Bronchodilator
  • Lung slices
  • Rosiglitazone

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