Targeting histone deacetylase 2 in chronic obstructive pulmonary disease treatment.
There is increasing evidence that histone acetylation plays a critical role in the regulation of inflammatory genes and in mediating the anti-inflammatory effects of corticosteroids. Inflammatory stimuli through transcription factors, such as NF-kappaB, recruit co-activator molecules with intrinsic histone acetyltransferase activity, leading to hyperacetylation of core histones and gene activation. Histone deacetylases (HDACs) reverse this process and suppress inflammatory genes. Corticosteroids, the most effective anti-inflammatory drugs so far available, recruit HDAC2 to activated inflammatory gene complexes through an interaction with glucocorticoid receptor and thus switch off activated inflammatory genes. In chronic obstructive pulmonary disease and in asthmatic patients who smoke, there is a reduction in HDAC2 activity and expression, resulting in amplification of inflammation and corticosteroid resistance. Therapeutic strategies to increase HDAC activity may, therefore, be expected to reduce inflammation and restore steroid responsiveness. These strategies include low doses of theophylline or antioxidants and nitric oxide synthase inhibitors. HDACs may be inhibited directly by siRNA and in the future by small-molecule activators may be discovered through high output screening. These drugs may represent a novel approach to treating chronic inflammatory diseases.
Barnes
Peter J
PJ
National Heart and Lung Institute, Imperial College School of Medicine, London SW3 6LY, UK. p.j.barnes@imperial.ac.uk
D000305:Adrenal Cortex Hormones / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000096:biosynthesis*; D006801:Humans; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000201:enzymology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*
D000305:Adrenal Cortex Hormones; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases