Novel Small Airway Bronchodilator Responses to Rosiglitazone in Mouse Lung Slices

Abstract

There is a need to identify novel agents that elicit small airway relaxation when b 2 -adrenoceptor agonists become ineffective in difficult-to-treat asthma. Because chronic treatment with the synthetic peroxisome proliferator activated receptor (PPAR)g 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 b-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. Concentrationdependent relaxation to RGZ was not altered by the b-adrenoceptor antagonist propranolol and was enhanced by ALB. RGZ-induced relaxation was mimicked by other synthetic PPARg agonists but not by the putative endogenous agonist 15-deoxy-PGJ 2 and was not prevented by the PPARg antagonist GW9662.

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

“…PCLS were prepared as previously described (3,6,9). Mice were killed with an overdose of sodium pentobarbitone (0.45 ml, 60 mg/ml ip).…”

“…In PCLS, RGZ elicited complete relaxation under conditions of impaired ␤-adrenoceptor agonist responsiveness, opposing contraction by inhibiting calcium oscillations and sensitivity (3). However, these novel direct dilator actions have yet to be confirmed when large and small airway reactivity to contractile agonists is altered by allergen challenge.…”

“…In BALB/c mice, treatment with either RGZ or CGZ inhibited OVA-induced airway inflammation and fibrosis as well as the development of AHR (14,32,35), with the effects of the synthetic PPAR␥ ligands mimicked by AdPPAR␥ (15, 17) and abrogated by GW9662 (14,15,17,35). Although RGZ also reduced the development of AHR in OVA-challenged C57BL/6 mice, the increase in BAL inflammatory cells in this mouse strain was not affected, suggesting that RGZ may also modulate AHR by a mechanism that is independent of inhibition of inflammatory cell recruitment to the airway (33).In addition to these inhibitory effects in models of chronic AAD, RGZ has been shown to elicit acute relaxation of mouse tracheal segments and intrapulmonary airways in precision cut lung slices (PCLS) precontracted with muscarinic agonists in vitro (3,12). In PCLS, RGZ elicited complete relaxation under conditions of impaired ␤-adrenoceptor agonist responsiveness, opposing contraction by inhibiting calcium oscillations and sensitivity (3).…”

“…In addition to these inhibitory effects in models of chronic AAD, RGZ has been shown to elicit acute relaxation of mouse tracheal segments and intrapulmonary airways in precision cut lung slices (PCLS) precontracted with muscarinic agonists in vitro (3,12). In PCLS, RGZ elicited complete relaxation under conditions of impaired ␤-adrenoceptor agonist responsiveness, opposing contraction by inhibiting calcium oscillations and sensitivity (3).…”

“…Numerous studies suggest that PPAR␥ ligands can inhibit allergen-induced inflammation and the development of airway remodeling and airway hyperresponsiveness (AHR) in vivo (reviewed in Ref. 8), as well as exert direct dilator effects on airway smooth muscle (ASM) in vitro (3,12).…”