Chest
Translating Basic Research Into Clinical PracticeMolecular Mechanisms of Combination Therapy With Inhaled Corticosteroids and Long-Acting β-Agonists
Section snippets
How Do β2-Agonists Work?
Understanding the reaction from combined therapy requires an understanding of the mechanism of action of each drug class. This mechanism is well known for the β2-agonists because the effect of short-acting β2-agonists had been well recognized for many years. Given that one of the major events in an episode of asthma is the constriction of the airway, largely due to contraction of the airway smooth muscle, the relaxation of the smooth muscle in response to a β2-agonist is of pivotal importance.
How Do ICSs Work?
The principal action of ICSs is that of modulation of the transcription of multiple genes. The majority of the glucocorticoid receptors (GRs) reside in the cytoplasm. After entry into the cell, ICSs bind to the GR, which then is activated and moved into the nucleus where it binds to specific DNA sequences termed glucocorticoid response elements (GREs). The result of this activation can be the inhibition of proinflammatory transcription factors or an increase in the transcription of
How Do LABAs Affect CS Activity?
Kaur et al11 reported that although CSs had no effect on β2-agonist-induced cAMP response-element-dependent transcription in human airway cells, GRE-dependent transcription induced by CSs was synergistically enhanced by LABAs. This study also provided in vitro evidence for a steroid-sparing effect of β2-agonists, in that maximal GRE-mediated responses were achieved at much lower concentrations of the CS in the presence of the β2-agonist. It has been reported2 that LABAs can activate the
What Is the Effect of ICSs on β2-Receptor Function?
It has been known for some time14 that CSs influence β2-receptor function and that this influence takes several forms. First, CSs can influence β2-receptor number by increasing the transcription of the β2-receptor gene and reversing the effect of long-term LABA exposure, which leads to decreased transcription.15 This function is particularly important for the inhibition by β2-agonists of mast-cell-mediator release, an effect that is subject to rapid desensitization.16 However, in some instances
How Do ICSs and LABAs Work Together To Inhibit Airway Responses?
In 2002, Roth et al13 examined the effect of ICSs and LABAs alone and in combination on proliferation control in nondiseased airway smooth muscle cells. The evident antiproliferative effect resulted from the stimulation of two transcription factors, namely, the GR and CCAAT enhancer-binding protein (C/EBP)-α, by both drug classes. C/EBP-α and the GR formed a complex that translocated to the nucleus. The downstream signaling occurred through stimulation of the p21(waf1/Cip1) gene. The combined
In Vivo Studies
Evidence for an interaction between the ICSs and LABAs also exists from in vivo studies in healthy nonsmokers and patients with mild asthma. Usmani et al28 demonstrated GR activation in sputum-derived epithelial cells after the administration of both ICSs and LABAs, and the combination of the two drugs was better than the steroid alone at increasing translocation of the GR to the nucleus. Inflammatory mediator release from sputum-isolated cells also was reduced by the combination of
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
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