Asthma diagnosis and treatment
Update on glucocorticoid action and resistance

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Extensive development of inhaled and oral glucocorticoids has resulted in highly potent molecules that have been optimized to target activity to the lung and minimize systemic exposure. These have proved highly effective for most asthmatic subjects, but despite these developments, there are a number of subjects with asthma who fail to respond to even high doses of inhaled or even oral glucocorticoids. Advances in delineating the fundamental mechanisms of glucocorticoid pharmacology, especially the concepts of transactivation and transrepression and cofactor recruitment, have resulted in better understanding of the molecular mechanisms whereby glucocorticoids suppress inflammation. The existence of multiple mechanisms underlying glucocorticoid insensitivity raises the possibility that this might indeed reflect different diseases with a common phenotype, and studies examining the efficacy of potential new agents should be targeted toward subgroups of patients with severe corticosteroid-resistant asthma who clearly require effective new drugs and other approaches to improved asthma control.

Section snippets

Structure of the GR and its gene

Glucocorticoids exert their effects by binding to a ubiquitously expressed 777-amino-acid GR that is localized to the cytoplasm of target cells. GR is a modular transcription factor in which specific domains play selective roles (Fig 1).4 Although unliganded GR is thought to remain in the cytoplasm, evidence with nuclear export inhibitors suggests that a rapid active cycling of GR between the nucleus and cytoplasm might occur.8, 9 2 GR isoforms (α and β) were originally described (Fig 2), with

Gene repression by GRs

In spite of the ability of glucocorticoids to induce gene transcription, the major anti-inflammatory effects of glucocorticoids are through repression of inflammatory and immune genes (Fig 4). Most glucocorticoid-repressible inflammatory genes do not posses negative GREs in their promoters, and the expression of some genes, such as prolactin and osteocalcin, are decreased on GR-GRE binding as a result of the GRE being positioned across a binding site for another transcription factor or across

Glucocorticoid resistance in asthma

Although glucocorticoids are highly effective in the control of asthma and other chronic inflammatory or immune diseases, a small proportion of patients with asthma fail to respond even to high doses of oral glucocorticoids.105 Resistance to the therapeutic effects of glucocorticoids is also recognized in other inflammatory and immune diseases, including rheumatoid arthritis and inflammatory bowel disease.106, 107 Glucocorticoid-resistant patients, although uncommon, present considerable

Molecular mechanisms of corticosteroid resistance

At a molecular level, resistance to the anti-inflammatory effects of glucocorticoids can be induced by several mechanisms, and these might differ between patients. The reduction in corticosteroid responsiveness observed in cells from these subjects has been ascribed to a reduced number of GRs, altered affinity of the ligand for GRs, reduced ability of the GRs to bind to DNA, or increased expression of inflammatory transcription factors, such as AP-1, that compete for DNA binding.108, 118

Immunomodulation

TH2 cytokines have also been proposed to play a role in severe CR asthma. A recent study has shown that CD4+ T cells from patients with CR asthma are less able to produce the anti-inflammatory cytokine IL-10 in response to dexamethasone than cells from patients with CS asthma.172 These data suggest that therapeutic administration of IL-10 or of high IL-10–producing T regulatory cells might be effective in CR asthma. Furthermore, the same group has reported that addition of vitamin D3 in

Management of glucocorticoid resistance

The management of patients with CR asthma poses a considerable challenge to the clinician. These patients are often subjected to the unwanted side effects of prolonged systemic glucocorticoid therapy in situations in which there is no evidence that it is exerting any appreciable benefit. A previous review in the Journal118 clearly shows in detail the stepwise algorithm for treating patients with CR asthma, and this is summarized here. As described earlier, similar percentages of patients

Conclusions

Enormous progress has been made in improving glucocorticoid treatment since the introduction of hydrocortisone as the first clinically used glucocorticoid in 1948. Extensive drug development has resulted in highly potent molecules, the pharmacokinetic profiles of which have been optimized to minimize systemic exposure and to target activity to the lung. The majority of asthmatic subjects of all disease severity respond well to these agents. Despite this, there are a number of subjects with

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    Work in our group is supported by Asthma UK, The British Lung Foundation, The Clinical Research Committee (Brompton Hospital), The Medical Research Council (UK), The National Institutes of Health (USA), The Wellcome Trust, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline (UK), Mitsubishi Pharma (Japan), Novartis, and Pfizer.

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