摘要：Inhaled glucocorticoids acting via the glucocorticoid receptor are a mainstay treatment option forindividuals with asthma. There is a consensus that the remedial actions of inhaled glucocorticoids aredue to their ability to suppress inflammation by modulating gene expression. While inhaledglucocorticoids are generally effective in asthma, there are subjects with moderate-to-severe diseasein whom inhaled glucocorticoids fail to provide adequate control. For these individuals, asthmaguidelines recommend that a long-acting b2-adrenoceptor agonist (LABA) be administeredconcurrently with an inhaled glucocorticoid. This so-called “combination therapy” is often effectiveand clinically superior to the inhaled glucocorticoid alone, irrespective of dose. LABAs, and anotherclass of drug known as phosphodiesterase 4 (PDE4) inhibitors, may also enhance the efficacy ofinhaled glucocorticoids in chronic obstructive pulmonary disease (COPD). In both conditions, thesedrugs 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 combinationtherapy, it remains unclear how an increase in cAMP enhances the clinical efficacy of an inhaledglucocorticoid. In this report, we provide a state-of-the-art appraisal, including unresolved andcontroversial issues, of how cAMP-elevating drugs and inhaled glucocorticoids interact at a molecularlevel to deliver enhanced anti-inflammatory benefit over inhaled glucocorticoid monotherapy. Wealso speculate on ways to further exploit this desirable interaction. Critical discussion of how thesetwo drug classes regulate gene transcription, often in a synergistic manner, is a particular focus.Indeed, because interplay between glucocorticoid receptor and cAMP signaling pathways maycontribute to the superiority of inhaled glucocorticoid/LABA combination therapy, understandingthis interaction may provide a logical framework to rationally design these multicomponenttherapeutics that was not previously possible.
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