Beta-Adrenoceptor Agonists Block Corticosteroid Inhibition in Eosinophils

Abstract

Although beta-adrenoceptor agonists are primary agents in therapy of asthma, epidemiological studies have suggested that frequent or prolonged used of these drugs could be associated with exacerbation of disease. Mechanisms of any adverse effects remain unclear although in vitro studies have suggested that beta-adrenoceptor agonists can block glucocorticoid actions. Because asthma is an inflammatory disease characterized by eosinophil infiltration of the airways, actions of beta-agonists and corticosteroids that alter eosinophil survival and mediator generation may be of importance. Eosinophil generation of superoxide anion, a potent mediator that can damage respiratory epithelium, was markedly increased after 2-24 h of in vitro beta-adrenoceptor agonist exposure. These proinflammatory effects are in contrast to inhibition of superoxide generation, which is observed with acute beta-agonist exposure. Corticosteroid treatment to reduce inflammation is combined with beta-agonist therapy in current asthma guidelines. Although dexamethasone independently decreased eosinophil superoxide anion generation, in the presence of beta-adrenoceptor agonist dexamethasone inhibition was minimal and not statistically significant. Eosinophil survival is a relevant factor to pulmonary inflammation. Although beta-adrenoceptor agonists did not independently increase eosinophil survival, glucocorticoid actions that increase apoptosis were blocked. Thus, in vitro beta-agonists can independently increase inflammatory mediator generation and block anti-inflammatory actions of corticosteroid.

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

“…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]. In marked contrast to our study and others, Nielson and Hadjokas [21], using prolonged incubation times and a lucigenin-dependent luminescence assay for superoxide quantitation, have shown that salmeterol and a non-specific β-agonist (isoproterenol) increased superoxide generation in human eosinophils stimulated in suspension by N-formyl-Met-Leu-Phe (FMLP). Moreover, they have shown that salmeterol, isoproterenol and salbutamol blocked the inhibitory effects of dexamethasone.…”

“…Our study demonstrates that BUD directly and dose dependently inhibits eosinophil superoxide. In agreement with our findings, Nielson and Hadjokas [21] also showed that dexamethasone inhibited superoxide generation in human eosinophils stimulated with FMLP. By contrast, dexamethasone did not inhibit superoxide generation in eosinophils stimulated by platelet-activating factor, however, 1 h incubation time was probably too short to induce a steroid effect [18].…”

“…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.…”

Regular salbutamol use increases CXCL8 responses in asthma: relationship to the eosinophil response

“…For example, addition of salbutamol to cultures of stimulated monocytes [35] or neutrophils [36] reduces their secretion of CXCL8/IL-8, although it increases or does not affect expression of this chemokine by transformed epithelial cells [23] or airway smooth muscle cells [37], respectively. Some b 2 -agonists can downregulate the expression by human mast cells [38] or eosinophils [39] of TNF or superoxide, respectively, and a single dose of salmeterol can inhibit allergen-induced changes in nasal mucosa vascular permeability, but does not reduce mast cell activation or cellular influx in vivo [40]. Conversely, prolonged in vitro exposure of eosinophils to b 2 -agonists increases cellular superoxide release [39].…”

“…Some b 2 -agonists can downregulate the expression by human mast cells [38] or eosinophils [39] of TNF or superoxide, respectively, and a single dose of salmeterol can inhibit allergen-induced changes in nasal mucosa vascular permeability, but does not reduce mast cell activation or cellular influx in vivo [40]. Conversely, prolonged in vitro exposure of eosinophils to b 2 -agonists increases cellular superoxide release [39]. Thus, the impact of salbutamol on cellular responses can vary substantially with the system employed.…”