Can the anti-inflammatory activities of β2-agonists be harnessed in the clinical setting?

Abstract

Beta2-adrenoreceptor agonists (β2-agonists) are primarily bronchodilators, targeting airway smooth muscle and providing critical symptomatic relief in conditions such as bronchial asthma and chronic obstructive pulmonary disease. These agents also possess broad-spectrum, secondary, anti-inflammatory properties. These are mediated largely, though not exclusively, via interactions with adenylyl cyclase-coupled β2-adrenoreceptors on a range of immune and inflammatory cells involved in the immunopathogenesis of acute and chronic inflammatory disorders of the airways. The clinical relevance of the anti-inflammatory actions of β2-agonists, although often effective in the experimental setting, remains contentious. The primary objectives of the current review are: firstly, to assess the mechanisms, both molecular and cell-associated, that may limit the anti-inflammatory efficacy of β2-agonists; secondly, to evaluate pharmacological strategies, several of which are recent and innovative, that may overcome these limitations. These are preceded by a consideration of the various types of β2-agonists, their clinical applications, and spectrum of anti-inflammatory activities, particularly those involving adenosine 3′,5′-cyclic adenosine monophosphate-activated protein kinase-mediated clearance of cytosolic calcium, and altered gene expression in immune and inflammatory cells.

Salmeterol Efficacy and Bias in the Activation and Kinase-Mediated Desensitization of β2-Adrenergic Receptors

“…Furthermore, the use of salmeterol in the clinic is now strictly indicated for use as an add-on to therapy with steroids. It has been appreciated that use of PDE4 inhibitors in the treatment of asthma and chronic obstructive pulmonary disease may be clinically important and synergize with glucocorticoids and LABA treatment to reduce the frequency of exacerbations, as recently discussed (Kaur et al, 2008;Nino et al, 2010;Cooper et al, 2011;Holden et al, 2011;Dekkers et al, 2012;Manetsch et al, 2013;Moodley et al, 2013;Theron et al, 2013;Giembycz and Newton, 2014;BinMahfouz et al, 2015). Our findings showing the dramatic effects of PDE inhibition on cAMP levels after either long-term or short-term salmeterol treatment support the importance of developing multidrug therapy that includes PDE inhibitors, LABAs, and steroids.…”

Evaluation of the anti-inflammatory effects of β-adrenoceptor agonists on human lung macrophages

“…In addition to bronchodilation, -agonists may also possess anti-inflammatory activity (Barnes, 2006;Theron et al, 2013). Both in vitro and in vivo studies suggest that -agonists may dampen inflammation although there are inconsistencies (Schild, 1937;O'Connor et al, 1994;Maris et al, 2004, Maris et al, 2005Bosmann et al, 2012;Wex et al, 2015).…”

The Beta-2-Adrenoreceptor Agonists, Formoterol and Indacaterol, but Not Salbutamol, Effectively Suppress the Reactivity of Human NeutrophilsIn Vitro

“…The study is focused on the effects of these agents on the proinflammatory activities of the human neutrophil, a cell type which not only expresses relatively high numbers of β 2ARs in comparison with other types of immune and inflammatory cells [5, 11], but which is also intimately involved in the immunopathogenesis of COPD [12, 13]. In addition, while several recent studies have addressed the anti-inflammatory interactions of indacaterol with human lung fibroblasts [14] and mast cells [15], the effects of this agent on human neutrophils have not been described.…”