Glucocorticoid-resistant asthma and novel anti-inflammatory drugs

► Resistance limits the effectiveness of glucocorticoid in chronic inflammation. ► Glucocorticoids target both inflammatory and structural cells in chronic inflammation. ► Reversal of glucocorticoid resistance in structural cells offers new drug targets. Synthetic glucocorticoids are among the most commonly used prescription medicines. Nevertheless, their clinical efficacy is accompanied by dose- and indication-limiting acute and chronic adverse effects. Intrinsic or acquired resistance to glucocorticoid actions may also limit clinical efficacy. In chronic inflammatory conditions there has been a considerable focus on understanding mechanism(s) of resistance in cells with a primary immune and/or inflammatory function. However, it has become increasingly accepted that a substantial part of the efficacy of glucocorticoid treatments derives from actions on ‘structural’ cell types (smooth muscle, fibroblasts, epithelia). In this article we review the mechanism of action of glucocorticoids on structural cells and contrast knowledge of resistance mechanisms between structural and inflammatory cell types, using asthma as an exemplar chronic inflammatory condition associated with glucocorticoid resistance.