Theophylline in chronic obstructive pulmonary disease: new horizons.
Although theophylline has side effects when used in bronchodilator doses, increasing evidence shows that it has significant antiinflammatory effects in chronic obstructive pulmonary disease at lower plasma concentrations. These antiinflammatory effects are unlikely to be accounted for by phosphodiesterase inhibition or adenosine receptor antagonism, which require higher concentrations. There is now evidence that theophylline at low therapeutic concentrations is an activator of histone deacetylases and that this activation enhances the antiinflammatory effect of corticosteroids. There appears to be a marked reduction in histone deacetylase-2 in macrophages and peripheral lung of patients with chronic obstructive pulmonary disease, which accounts for amplified inflammation and steroid resistance. Theophylline has been shown to restore steroid sensitivity in vitro. The effect of theophylline on histone deacetylase activity appears to be enhanced by oxidative stress. The mechanism whereby theophylline activates histone deacetylase is not yet known, but it does not involve other known actions of theophylline that account for its side effects. Better understanding of the molecular basis for the action of theophylline might lead to the development of novel drugs.
Barnes
Peter J
PJ
Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK. p.j.barnes@imperial.ac.uk
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001993:Bronchodilator Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004347:Drug Interactions; D004351:Drug Resistance; D004789:Enzyme Activation / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000378:metabolism; D013806:Theophylline / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D010726:Phosphodiesterase Inhibitors; D013806:Theophylline; D006655:Histone Deacetylases