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Abstract
Glucocorticoid resistance or insensitivity is a major barrier to the treatment of
several common inflammatory diseases-including chronic obstructive pulmonary disease
and acute respiratory distress syndrome; it is also an issue for some patients with
asthma, rheumatoid arthritis, and inflammatory bowel disease. Several molecular mechanisms
of glucocorticoid resistance have now been identified, including 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, and 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 kappaB, 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 of this approach are 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-delta inhibitors,
and inhibition of macrophage migration inhibitory factor and P-glycoprotein.