Differential Effects of Short-Acting β₂-Agonists on Human Granulocyte Functions

Abstract

Background: β₂-Adrenergic agonists play a pivotal role in the management of bronchial asthma. Although the major effect of short-acting β₂-agonists on the airway is relaxation of smooth muscles, they may also have several effects on surrounding immunomodulatory cells. Methods: We examined whether widely used short-acting β₂-agonists differ in their ability to modulate granulocyte functions, such as superoxide anion (O₂^–) production and degranulation. Results: Procaterol (PC), a full agonist, significantly inhibited both O₂^– production by granulocytes (neutrophils and eosinophils) and their degranulation at the clinically relevant concentrations, whereas salbutamol and tulobuterol (partial agonists) showed smaller effects. PC inhibited N-formyl methionyl-leucyl-phenylalanine-induced O₂^– production and peroxidase release, but failed to inhibit responses induced by phorbol 12-myristate 13-acetate and/or opsonized zymosan. Exposure to 5 × 10^–8M PC for 120 min resulted in approximately 50% inhibition of O₂^– production and degranulation of neutrophils. The effects of β₂-agonists were more obvious in neutrophils than in eosinophils. A selective β₂-receptor antagonist, ICI-118551, reversed the inhibitory effect of β₂-agonists (PC, salbutamol, tulobuterol B) on N-formyl methionyl-leucyl-phenylalanine-induced O₂^– production. Conclusions: These results suggest that β₂-agonists had an inhibitory effect on granulocyte functions, mainly mediated viareceptors and their efficacy. Our observations support that β₂-agonists with a rapid onset of action and high intrinsic efficacy (short-acting and full agonists) may be optimal for the rescue therapy against acute asthma attack and sedation of its airway inflammation in an early phase.

Cooperative Inhibitory Effects of Budesonide and Formoterol on Eosinophil Superoxide Production Stimulated by Bronchial Epithelial Cell Conditioned Medium

“…The direct inhibitory effects of FORM on superoxide production shown in the Eos assay are in agreement with previous in vitrostudies with FORM and other β 2 -agonists in adherent eosinophils and eosinophils in suspension [16,17,18,19]. This suggests that the inhibitory effects of β 2 -agonists can occur independently of the effects on cell adhesion, even though cell adhesion can play a crucial role in modulating eosinophil superoxide [38,43,44,45,46].…”

“…Since the generation of superoxide by eosinophils in vitro and its pharmacological control is stimulus dependent [16,17,18,19], we have chosen bronchial epithelial cell-derived CM to stimulate eosinophils and thereby mimic a possible activation mechanism in vivo. That epithelial GM-CSF was the responsible mediator in CM was indicated by its presence at a sufficient concentration (∼1 ng/ml) to stimulate maximal superoxide generation and by the inhibitory effects of GM-CSF-neutralising antibodies.…”

“…Nevertheless, in the present study (3 h incubation) and those of Ezeamuzie et al [16,17,18](1 h incubation), effective inhibition of superoxide in human eosinophils, activated by a wide range of stimuli, was achieved with a number of β-agonists. Moreover, Yasui et al [19] have recently demonstrated that superoxide production by FMLP-stimulated human eosinophils in suspension was inhibited by various short-acting β 2 -agonists progressively with incubation time, reaching plateau at 2 h. Of note, the specificity of lucigenin and its suitability for the quantitation of superoxide in cellular systems has been questioned because it was shown that lucigenin via auto-oxidation may itself act as a source of superoxide anion [47, 48]. Thus, findings using this technique should be interpreted with caution.…”

“…One of the controversies regards the ability of LABAs (and short-acting β 2 -agonists) to inhibit the stimulated generation of superoxide anion and other reactive oxygen species (ROS) in eosinophils, which are pivotal effector cells in asthma. Inhibitory effects of both short-acting β 2 -agonists and LABAs on ROS generation have been reported in several in vitro studies [15,16,17,18,19], and for a LABA (FORM) in an in vivo study [20]. In contrast, in another in vitro study [21] a LABA (salmeterol) not only increased superoxide generation by activated human eosinophils, but similarly to the short-acting salbutamol also blocked the inhibitory effects of dexamethasone on ROS generation.…”

Therapeutic Efficacy of a H4 Receptor Antagonist in Humans: A Milestone in Histamine Research

“…In this context, it would be desirable to see future studies on pruritus that describe how dermatological preparations of selective H 1 and H 4 receptor agonists (for review on such compounds, see Seifert et al, 2013) selectively induce the wheal and flare reactions and pruritus, respectively, and how H 2 receptor agonists may be used to reduce pruritus symptoms. It is also worthwhile to explore b 2 -adrenoceptor agonists as adjunct to H 4 receptor antagonists because activation of the b 2 -adrenoceptors mediates anti-inflammatory effects and b 2 -adrenoceptor agonists are already approved for asthma therapy (Yasui et al, 2006).…”