Abstract
A new long-acting β2-agonist, formoteroi, has been reported to have a greater efficacy and duration of action in asthmatic patients as compared to conventional (β2-agonists. We recently demonstrated that formoteroi inhibited antigen-induced late asthmatic response (LAR) and accompanying airway eosi- nophilia in guinea pigs. In this study, we investigated the direct effect of formoteroi in vitro on human eosinophil function, focusing on platelet-activating factor (PAF)-induced eosinophil chemotaxis and eosinophil cationic protein (ECP) release. Purified normodense eosinophils were separated by discontinuous gradient from 12 mild asthmatic patients. Formoteroi in concentrations of 1-100 μΜ significantly inhibited PAF-induced eosinophil chemotaxis in a dose-dependent manner with a concentration of drug required to produce 50% inhibition (IC50) of 10.16 μΜ; % inhibition: 22.9±13.0% (1 μΜ). 51.6 ± 12.7% (10 μΜ), 75.0 ± 11.3% (100 μΜ). When formyl-methionyl-leueyl-phenylamine (FMLP) was used as a ehemoattractant, a similar inhibition of eosinophil chemotaxis by formoteroi was observed; % inhibition: 13.1 ± 5.0% (1 μΜ). 47.7 ±7.6% (10 μΜ). 65.5 ± 16.5% (100 μM). A conventional β2-agonist, salbutamol, at doses to 100 μΜ did not show any inhibitory effects on PAF-induced eosinophil chemotaxis. Formoteroi in concentrations of 1-100 μΜ also significantly inhibited PAF-induced ECP release from eosinophils; % inhibition: 21.7 ± 9.0% (1 μΜ), 39.3 ± 7.4% (10 μΜ), 39.6 ± 8.4% (100 μΜ).In the presence of phosphodiesterase inhibitors, theophylline or isobutylmethyl xanthine (IBMX), the inhibition by formoteroi on PAF-induced ECP release was enhanced. The combination of formoteroi (10 μΛ7) and IBMX (10 μΜ) achieved 70.3 ± 7.6% inhibition. Salbutamol in concentrations of 0.1 -100 μΜ failed to inhibit PAF-induced ECP release. The inhibition of PAF-induced eosinophil chemotaxis and ECP release by formoteroi were not abolished by propranolol. This comparison between formoteroi and salbutamol suggestes that formoteroi is not only a longer-acting β2-agonist but may have more beneficial properties to prevent eosinophil-mediated inflammatory processes of LAR than conventional β2-agonists.