Molecular mechanisms of combination therapy with inhaled corticosteroids and long-acting beta-agonists.
The treatment of asthma relies on the use of the following two major drug classes: beta(2)-agonists, both short acting and long acting; and corticosteroids (CSs). Although the properties of each drug class are well described, their use in combination delivered either separately or through one device has provided some clear and important clinical advantages. The mechanisms underlying these interactions have emerged as novel and provocative. beta(2)-Agonists can stimulate the glucocorticoid receptor (GR) and promote its translocation to the nucleus, resulting in increased CS-mediated gene transcription. In structural airway cells, such as fibroblasts and smooth muscle, this gene transcription is associated with the formation of a complex between the GR and another transcription factor, CCAAT enhancer-binding protein (C/EBP)-alpha. Airway smooth muscle cells from persons with asthma are deficient in C/EBP-alpha, which may explain the finding that CSs do not inhibit the proliferation of these cells in vitro. Whether this deficiency can explain the increased bulk of muscle in the asthmatic airway remains to be established. beta(2)-Agonists can inhibit mast cell mediator release, but this response is susceptible to desensitization, a process that CSs can inhibit. CSs also can increase the transcription of the beta(2)-receptor gene in the lung and the nasal mucosa. These effects of CSs mitigate against the reduced transcription of beta(2)-receptors, which occurs as a consequence of long-term beta(2)-agonist administration. Delineation of the exact mechanisms underlying these effects will ensure rational, direct therapy.
Black
Judith L
JL
School of Medical Sciences (Pharmacology) and Woolcock Institute of Medical Research, Sydney Medical School, The University of Sydney, NSW, Australia. Electronic address: judblack@med.usyd.edu.au.
Oliver
Brian G G
BGG
School of Medical Sciences (Pharmacology) and Woolcock Institute of Medical Research, Sydney Medical School, The University of Sydney, NSW, Australia.
Roth
Michael
M
Pulmonary Cell Research, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage* / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage* / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D004359:Drug Therapy, Combination; D006801:Humans; D009130:Muscle, Smooth / Q000187:drug effects; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D012137:Respiratory System / Q000187:drug effects
D000305:Adrenal Cortex Hormones; D000318:Adrenergic beta-Agonists; D003692:Delayed-Action Preparations; D011943:Receptors, Adrenergic, beta