Pharmacology and Therapeutics of Asthma and COPD

Peter J. Barnes, Barnes, Peter J.

Glucocorticosteroids are the most effective anti-inflammatory therapy for asthma but are relatively ineffective in COPD. Glucocorticoids are broad-spectrum anti-inflammatory drugs that suppress inflammation via several molecular mechanisms. Glucocorticoids suppress the multiple inflammatory genes that are activated in asthma by reversing histone acetylation of activated inflammatory genes through binding of ligand-bound glucocorticoid receptors (GR) to coactivator molecules and recruitment of histone deacetylase-2 (HDAC2) to the activated inflammatory gene transcription complex (trans-repression). At higher concentrations of glucocorticoids GR homodimers interact with DNA recognition sites to activate transcription through increased histone acetylation of anti-inflammatory genes and transcription of several genes linked to glucocorticoid side effects (trans-activation). Glucocorticoids also have post-transcriptional effects and decrease stability of some proinflammatory mRNAs. Decreased glucocorticoid responsiveness is found in patients with severe asthma and asthmatics who smoke, as well as in all patients with COPD. Several molecular mechanisms of glucocorticoid resistance have now been identified which involve phosphorylation and other post-translational modifications of GR. HDAC2 is markedly reduced in activity and expression as a result of oxidative/nitrative stress and pi3 kinase-δ inhibition, so that inflammation is resistant to the anti-inflammatory actions of glucocorticoids. Dissociated glucocorticoids and selective GR modulators which show improved trans-repression over trans-activation effects have been developed to reduce side effects, but so far it has been difficult to dissociate anti-inflammatory effects from adverse effects. In patients with glucocorticoid resistance alternative anti-inflammatory treatments are being investigated as well as drugs that may reverse the molecular mechanisms of glucocorticoid resistance.