title: Airway smooth muscle as a target of glucocorticoid action in the treatment of asthma.
abstract: Glucocorticoids are highly effective in the control of asthma and suppression of airway inflammation. The cellular and molecular mechanisms involved in the anti-inflammatory actions of glucocorticoids are becoming clearer. Although it is apparent that glucocorticoids have effects on many aspects of inflammation, it is not certain which actions on which cell types are the most critical in controlling asthma. Airway smooth muscle cells represent a significant proportion of all cells present in the airways and might therefore be expected to be a prominent cellular target for inhaled steroids. Despite this, little is known of the action of glucocorticoids on airway smooth muscle. It is becoming clear that in addition to its contractile properties, airway smooth muscle can potentially contribute to the pathogenesis of asthma by increased proliferation and by expression and secretion of pro-inflammatory cytokines and mediators, which in turn may lead to the activation and recruitment of key inflammatory cells in the airways. This review examines the action of glucocorticoids on some of the diverse functions of airway smooth muscle that are implicated in remodeling of the airways in asthma. Glucocorticoids either directly or indirectly modulate contraction of airway smooth muscle by suppressing agonist-induced increases in intracellular calcium levels or by downregulating or uncoupling receptors linked to contraction (e.g., muscarinic M2 or M3, histamine H1 receptors). In addition, glucocorticoids may augment relaxation of airway smooth muscle by increasing activation of either cyclic AMP-dependent (e.g., increased expression of beta2-adrenoceptors, reduced homologous desensitization of beta2-adrenoceptors) or AMP-independent mechanisms (e.g., increased Na+/K+ electrogenic pump activity). In addition to their effects on contraction, glucocorticoids are also effective antiproliferative agents in airway smooth muscle, but under some circumstances may also contribute to proliferation by inhibiting the antiproliferative effect of high concentrations of tumor necrosis factor alpha in these cells. Glucocorticoids also suppress induction of cyclooxygenase-2 in human airway smooth muscle cells and the subsequent synthesis and release of arachidonic acid metabolites, particularly prostaglandin E2. The potential of airway smooth muscle to recruit and activate pro-inflammatory cells such as the eosinophil may also be reduced by glucocorticoids, as they are effective in preventing the release of several cytokines (e.g., RANTES, interleukin-8, and granulocyte macrophage colony-stimulating factor). The possibility exists that as we begin to understand and speculate more about the likely role of airway smooth muscle in the pathogenesis of asthma, it may be necessary to reconsider airway smooth muscle as an important cellular target for the action of glucocorticoids in the treatment of asthma.
authors.affiliation: Department of Allergy and Respiratory Medicine, UMDS, Thomas Guy House, Guy's Hospital, London, United Kingdom. s.hirst@umds.ac.uk
authors.forename: S J
authors.initials: SJ
authors.lastname: Hirst
authors.forename: T H
authors.initials: TH
authors.lastname: Lee
mesh_terms: D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D005938:Glucocorticoids