Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase.
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.
Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, London SW3 6LY, UK. p.j.barnes@imperial.ac.uk
Peter J
PJ
Barnes
Kazuhiro
K
Ito
Ian M
IM
Adcock
D000305:Adrenal Cortex Hormones / Q000494:pharmacology / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004351:Drug Resistance / Q000235:genetics / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology*; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D030421:Peroxynitrous Acid / Q000502:physiology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000378:metabolism; D012097:Repressor Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012907:Smoking / Q000009:adverse effects; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D012097:Repressor Proteins; D030421:Peroxynitrous Acid; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases