Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase

Lancet. 2004 Feb 28;363(9410):731-3. doi: 10.1016/S0140-6736(04)15650-X.


By contrast with patients with asthma, those with chronic obstructive pulmonary disease (COPD) are poorly responsive to the anti-inflammatory actions of corticosteroids, and these drugs provide little clinical benefit. In both diseases, multiple inflammatory genes are activated, which results from acetylation of core histones around which DNA is wound. This acetylation opens up the chromatin structure allowing gene transcription and synthesis of inflammatory proteins to proceed. Corticosteroids recruit histone deacetylase 2 (HDAC2) to the actively transcribing gene, which reverses this process and switches off inflammatory gene transcription. We propose that in patients with COPD, HDAC2 function is impaired by cigarette smoking and oxidative stress, leading to a pronounced reduction in responsiveness to corticosteroids. Oxidative stress could generate peroxynitrite, which impairs HDAC2 activity through nitration of critical tyrosine residues. This hypothesis raises the possibility that novel therapeutic approaches might unlock this corticosteroid resistance, leading to more effective anti-inflammatory treatments for COPD and other severe inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Adrenal Cortex Hormones / pharmacology
  • Adrenal Cortex Hormones / therapeutic use*
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use*
  • Drug Resistance / genetics
  • Drug Resistance / physiology*
  • Gene Silencing / physiology*
  • Histone Deacetylase 2
  • Histone Deacetylases / drug effects
  • Histone Deacetylases / genetics
  • Histone Deacetylases / physiology*
  • Humans
  • Inflammation Mediators / physiology
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Peroxynitrous Acid / physiology
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Pulmonary Disease, Chronic Obstructive / metabolism
  • Repressor Proteins / drug effects
  • Repressor Proteins / genetics
  • Repressor Proteins / physiology*
  • Smoking / adverse effects
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology


  • Adrenal Cortex Hormones
  • Anti-Inflammatory Agents
  • Inflammation Mediators
  • Repressor Proteins
  • Peroxynitrous Acid
  • Histone Deacetylase 2
  • Histone Deacetylases