Molecular effects of inhaled glucocorticoid therapy in asthma
- Peter J Barnes, DM, DSc, FRCP, FRS
Peter J Barnes, DM, DSc, FRCP, FRS
- Editor-in-Chief — Pulmonary and Critical Care Medicine
- Section Editor — Asthma
- Professor of Medicine
- National Heart and Lung Institute, Imperial College, London
- Section Editors
- Bruce S Bochner, MD
Bruce S Bochner, MD
- Editor-in-Chief — Allergy and Immunology
- Section Editor — Adult Allergy; Asthma
- Samuel M Feinberg Professor of Medicine
- Northwestern University Feinberg School of Medicine
- Robert A Wood, MD
Robert A Wood, MD
- Editor-in-Chief — Allergy and Immunology
- Section Editor — Pediatric Allergy
- Professor of Pediatrics
- Johns Hopkins University School of Medicine
Inhaled glucocorticoids (ie, glucocorticosteroids, corticosteroids, steroids) suppress airway inflammation by activating anti-inflammatory genes, switching off inflammatory gene expression, and inhibiting inflammatory cells. In addition, they enhance beta 2 adrenergic signaling by increasing beta 2-receptor expression and function. The net effect is control of the symptoms and signs of asthma in most patients.
The molecular effects of inhaled glucocorticoids in asthmatic airways are discussed in this topic review. In addition, the molecular determinants of glucocorticoid sensitivity are reviewed. The pharmacology of glucocorticoids, the role of inhaled glucocorticoids in the management of asthma, and the potential adverse effects of inhaled glucocorticoids are presented separately. (See "Pharmacologic use of glucocorticoids" and "Determinants of glucocorticoid dosing" and "An overview of asthma management" and "Asthma in children younger than 12 years: Initiating therapy and monitoring control" and "Mechanisms and clinical implications of glucocorticoid resistance in asthma" and "Major side effects of inhaled glucocorticoids".)
SUPPRESSION OF INFLAMMATION
Discoveries related to gene transcription have improved our understanding of the mechanisms by which inhaled glucocorticoids suppress airway inflammation [1,2]. These mechanisms include anti-inflammatory gene activation and switching off inflammatory gene expression, which alter the expression of inflammatory and anti-inflammatory enzymes, receptors, cytokines, adhesion molecules, and chemokines. The net effect is decreased inflammatory cell recruitment, survival, and accumulation.
Anti-inflammatory gene activation — There are two types of glucocorticoid receptors (GR), GR alpha and GR beta. Glucocorticoid action is facilitated by GR alpha, but potentially inhibited by GR beta.
●GR alpha – Glucocorticoids passively diffuse across the cell membrane and bind to GR alpha in the cytoplasm . The glucocorticoid/GR alpha complex (ie, activated GR) rapidly translocates into the nucleus. There, the activated GR form dimers, which bind to glucocorticoid response elements (GREs) within the promoter of glucocorticoid-responsive genes. There are positive and negative GREs.
Interaction with positive GREs stimulates gene transcription. Such genes usually encode anti-inflammatory proteins . As an example, glucocorticoids stimulate expression of secretory leukoprotease inhibitor and mitogen-activated protein kinase phosphatase-1 (MKP-1), which inhibit mitogen-activated protein (MAP) kinase pathways (figure 1) . Interaction with positive GREs appears to account for most of the side effects of glucocorticoids . As an example, binding the GR to the promoter site on the osteocalcin gene interferes with its transcription, resulting in reduced expression and reduction in bone synthesis.
Interaction with negative GREs suppresses gene transcription, but there are only a few examples of reduced expression of inflammatory genes through interaction with negative GREs, indicating that other molecular mechanisms are involved in the suppression of inflammation.
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