Chest
Volume 136, Issue 4, October 2009, Pages 1095-1100
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Translating Basic Research Into Clinical Practice
Molecular Mechanisms of Combination Therapy With Inhaled Corticosteroids and Long-Acting β-Agonists

https://doi.org/10.1378/chest.09-0354Get rights and content

The treatment of asthma relies on the use of the following two major drug classes: β2-agonists, both short acting and long acting; and corticosteroids (CSs). Although the properties of each drug class are well described, their use in combination delivered either separately or through one device has provided some clear and important clinical advantages. The mechanisms underlying these interactions have emerged as novel and provocative. β2-Agonists can stimulate the glucocorticoid receptor (GR) and promote its translocation to the nucleus, resulting in increased CS-mediated gene transcription. In structural airway cells, such as fibroblasts and smooth muscle, this gene transcription is associated with the formation of a complex between the GR and another transcription factor, CCAAT enhancer-binding protein (C/EBP)-α. Airway smooth muscle cells from persons with asthma are deficient in C/EBP-α, which may explain the finding that CSs do not inhibit the proliferation of these cells in vitro. Whether this deficiency can explain the increased bulk of muscle in the asthmatic airway remains to be established. β2-Agonists can inhibit mast cell mediator release, but this response is susceptible to desensitization, a process that CSs can inhibit. CSs also can increase the transcription of the β2-receptor gene in the lung and the nasal mucosa. These effects of CSs mitigate against the reduced transcription of β2-receptors, which occurs as a consequence of long-term β2-agonist administration. Delineation of the exact mechanisms underlying these effects will ensure rational, direct therapy.

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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