Molecular mechanisms of antiasthma therapy.
Recently there has been a much greater understanding of the molecular mechanisms involved in the actions of antiasthma therapy. beta 2-agonists are the most effective bronchodilators and act predominantly on airway smooth muscle. Recent evidence suggests that beta 2-receptors in airway smooth muscle are coupled directly to maxi-K channels and may thereby bronchodilate without an increase in cyclic AMP. The issue of beta-receptor tolerance has been reawakened by the recognition that the protective effects of beta 2-agonists against bronchoconstrictor stimuli may become tolerant. Inhaled glucocorticoids are the mainstay of treatment in patients with chronic asthma. They suppress asthmatic inflammation predominantly by reducing transcription of genes coding for inflammatory mediators (particularly cytokines) and enzymes (inducible NO synthase, inducible cyclo-oxygenase). The inhibition of gene transcription is mediated predominantly by inhibition of transcription factors, such as activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappa B). There may be an abnormal activation of AP-1 in steroid-resistant asthma, and high concentrations of beta 2-agonists may induce a secondary resistance by an interaction between the transcription factor CREB and the glucocorticoid receptor. Theophylline may have immunomodulatory effects that are more important than its bronchodilator action. Some effects of theophylline are mediated via inhibition of phosphodiesterases and several PDE IV inhibitors are currently undergoing evaluation in asthma.
Department of Thoracic Medicine, National Heart and Lung Institute, London, UK.
P J
PJ
Barnes
D000318:Adrenergic beta-Agonists / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D013806:Theophylline / Q000627:therapeutic use; D014157:Transcription Factors / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D005938:Glucocorticoids; D014157:Transcription Factors; D013806:Theophylline