Lancet review: Glucocorticoid resistance in inflammatory diseases

Glucocorticoid resistance or insensitivity is a major barrier to the treatment of several common inflammatory diseases:

- COPD
- acute respiratory distress syndrome
- some patients with asthma, rheumatoid arthritis, and inflammatory bowel disease


Chemical structure of fluticasone propionate, a glucocorticoid. Image source: Wikipedia, public domain.

Several molecular mechanisms of glucocorticoid resistance have now been identified:

- activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines
- excessive activation of the transcription factor activator protein 1
- reduced histone deacetylase-2 (HDAC2) expression
- raised macrophage migration inhibitory factor
- increased P-glycoprotein-mediated drug efflux

Patients with glucocorticoid resistance can be treated with alternative broad-spectrum anti-inflammatory treatments, such as calcineurin inhibitors and other immunomodulators, or novel anti-inflammatory treatments, such as inhibitors of phosphodiesterase 4 or nuclear factor κB, although these drugs are all likely to have major side-effects.

An alternative treatment strategy is to reverse glucocorticoid resistance by blocking its underlying mechanisms. Some examples:

- inhibition of p38 MAP kinase
- use of vitamin D to restore interleukin-10 response
- activation of HDAC2 expression by use of theophylline, antioxidants, or phosphoinositide-3-kinase-δ inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein

References:
Lancet Review: Glucocorticoid resistance in inflammatory diseases. The Lancet, Volume 373, Issue 9678, Pages 1905 - 1917, 30 May 2009.