Pharmacological strategies for improving the efficacy and therapeutic ratio of glucocorticoids in inflammatory lung diseases

Glucocorticoids are widely used to treat various inflammatory lung diseases. Acting via the glucocorticoid receptor (GR), they exert clinical effects predominantly by modulating gene transcription. This may be to either induce (transactivate) or repress (transrepress) gene transcription. However, certain individuals, including those who smoke, have certain asthma phenotypes, chronic obstructive pulmonary disease (COPD) or some interstitial diseases may respond poorly to the beneficial effects of glucocorticoids. In these cases, high dose, often oral or parental, glucocorticoids are typically prescribed. This generally leads to adverse effects that compromise clinical utility. There is, therefore, a need to enhance the clinical efficacy of glucocorticoids while minimizing adverse effects. In this context, a long-acting β2-adrenoceptor agonist (LABA) can enhance the clinical efficacy of an inhaled corticosteroid (ICS) in asthma and COPD. Furthermore, LABAs can augment glucocorticoid-dependent gene expression and this action may account for some of the benefits of LABA/ICS combination therapies when compared to ICS given as a monotherapy. In addition to metabolic genes and other adverse effects that are induced by glucocorticoids, there are many other glucocorticoid-inducible genes that have significant anti-inflammatory potential. We therefore advocate a move away from the search for ligands of GR that dissociate transactivation from transrepression. Instead, we submit that ligands should be functionally screened by virtue of their ability to induce or repress biologically-relevant genes in target tissues. In this review, we discuss pharmacological methods by which selective GR modulators and “add-on” therapies may be exploited to improve the clinical efficacy of glucocorticoids while reducing potential adverse effects.