Oxidative stress and steroid resistance in asthma and COPD: pharmacological manipulation of HDAC-2 as a therapeutic strategy.
Insensitivity to corticosteroid treatment in inflammatory conditions, such as asthma and chronic obstructive pulmonary disease, present considerable management problems and cost burdens to health services. Oxidative stress is a major component of chronic inflammation and can have a significant suppressive effect on corticosteroid efficacy. Recent advances in the understanding of both the mechanisms of corticosteroid action and corticosteroid insensitivity have provided hope for a therapeutic strategy of restoring corticosteroid sensitivity. Histone deacetylase 2 (HDAC-2) plays a pivotal role in corticosteroid action and is reduced in many cases of steroid insensitivity. Moreover, it has shown that oxidative stress can be responsible for this reduction in HDAC-2 activity. Two structurally different compounds; methyl-xanthine theophylline and polyphenol curcumin restore HDAC activity, thereby restoring corticosteroid function. Low, subbronchodilator doses of theophylline can also act as corticosteroid-sparing drugs in asthmatics. Although these compounds appear to restore corticosteroid function and may initially provide therapeutic potential, they lack specificity and the mechanism of their action is unknown. Once their mechanisms of action are established, it is likely that derivatives of these compounds may be used as a therapeutic strategy to restore corticosteroid insensitivity in the future.
Marwick
John A
JA
Novartis Institute For Biomedical Research, Respiratory Disease Area, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, UK.
Ito
Kazuhiro
K
Adcock
Ian M
IM
Kirkham
Paul A
PA
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology*; D016503:Drug Delivery Systems / Q000379:methods; D004351:Drug Resistance; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000201:enzymology*; D012097:Repressor Proteins / Q000502:physiology*
D000305:Adrenal Cortex Hormones; D012097:Repressor Proteins; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases