Overcoming steroid unresponsiveness in airways disease

Ian M. Adcock, Pai Chien Chou, Andrew Durham, Paul Ford

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Most of the patients with asthma are found to be successfully treated with conventional therapy. However, there are a small proportion of asthmatic patients who fail to respond to corticosteroids even at high doses or with supplementary therapy. In addition, even high doses of corticosteroids have a minimal effect on the inexorable decline in lung function in COPD (chronic obstructive pulmonary disease) and only a small effect in reducing exacerbations. Corticosteroid-insensitivity therefore presents a profound management problem. Corticosteroids act through a cytosolic receptor [GR (glucocorticoid receptor)], which is activated and translocates to the nucleus. Once in the nucleus, it either binds to DNA and switches on the expression of anti-inflammatory genes or represses the activity of distinct signalling pathways such as NF-κB (nuclear factor κB), AP-1 (activator protein-1) or MAPKs (mitogen-activated protein kinases). This latter step requires the recruitment of co-repressor molecules. A failure to respond to corticosteroids may therefore result from lack of binding to GR, reduced GR expression, lack of co-repressor activity or enhanced activation of inflammatory pathways. These events can be modulated by oxidative stress or high levels of inflammatory cytokines, which may lead to a reduced clinical outcome. Understanding the molecular mechanisms of GR action, and inaction, may lead to the development of new anti-inflammatory drugs or reverse the relative corticosteroid-insensitivity that is characteristic of these diseases.

Original languageEnglish
Pages (from-to)824-829
Number of pages6
JournalBiochemical Society Transactions
Volume37
Issue number4
DOIs
Publication statusPublished - Sep 29 2009
Externally publishedYes

Fingerprint

Adrenal Cortex Hormones
Steroids
Co-Repressor Proteins
Anti-Inflammatory Agents
Repressor Proteins
Pulmonary diseases
Oxidative stress
Glucocorticoid Receptors
Transcription Factor AP-1
Mitogen-Activated Protein Kinases
Chronic Obstructive Pulmonary Disease
Oxidative Stress
Asthma
Genes
Chemical activation
Switches
Cytokines
Lung
DNA
Therapeutics

Keywords

  • Asthma
  • Chronic obstructive pulmonary disease (COPD)
  • Corticosteroid
  • Mitogen-activated protein kinase (MAPK)
  • Steroid
  • Theophylline

ASJC Scopus subject areas

  • Biochemistry

Cite this

Overcoming steroid unresponsiveness in airways disease. / Adcock, Ian M.; Chou, Pai Chien; Durham, Andrew; Ford, Paul.

In: Biochemical Society Transactions, Vol. 37, No. 4, 29.09.2009, p. 824-829.

Research output: Contribution to journalArticle

Adcock, Ian M. ; Chou, Pai Chien ; Durham, Andrew ; Ford, Paul. / Overcoming steroid unresponsiveness in airways disease. In: Biochemical Society Transactions. 2009 ; Vol. 37, No. 4. pp. 824-829.
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