Overcoming steroid unresponsiveness in airways disease

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

Research output: Contribution to journalArticle

12 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

Keywords

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

ASJC Scopus subject areas

  • Biochemistry

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