Inhaled
glucocorticoids acting via the
glucocorticoid receptor are a mainstay treatment option for individuals with
asthma. There is a consensus that the remedial actions of inhaled
glucocorticoids are due to their ability to suppress
inflammation by modulating gene expression. While inhaled
glucocorticoids are generally effective in
asthma, there are subjects with moderate-to-severe disease in whom inhaled
glucocorticoids fail to provide adequate control. For these individuals,
asthma guidelines recommend that a long-acting β2-adrenoceptor agonist (LABA) be administered concurrently with an inhaled
glucocorticoid. This so-called "combination
therapy" is often effective and clinically superior to the inhaled
glucocorticoid alone, irrespective of dose. LABAs, and another class of
drug known as
phosphodiesterase 4 (
PDE4) inhibitors, may also enhance the efficacy of inhaled
glucocorticoids in
chronic obstructive pulmonary disease (
COPD). In both conditions, these drugs are believed to work by elevating the concentration of cyclic adenosine-3',5'-monophosphate (cAMP) in target cells and tissues. Despite the success of inhaled
glucocorticoid/LABA combination
therapy, it remains unclear how an increase in cAMP enhances the clinical efficacy of an inhaled
glucocorticoid. In this report, we provide a state-of-the-art appraisal, including unresolved and controversial issues, of how cAMP-elevating drugs and inhaled
glucocorticoids interact at a molecular level to deliver enhanced anti-inflammatory benefit over inhaled
glucocorticoid monotherapy. We also speculate on ways to further exploit this desirable interaction. Critical discussion of how these two
drug classes regulate gene transcription, often in a synergistic manner, is a particular focus. Indeed, because interplay between
glucocorticoid receptor and cAMP signaling pathways may contribute to the superiority of inhaled
glucocorticoid/LABA combination
therapy, understanding this interaction may provide a logical framework to rationally design these multicomponent
therapeutics that was not previously possible.