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This Article Full Text Full Text (PDF) All Versions of this Article: 296/4/L693    most recent 90446.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kassel, K. M. Articles by Toews, M. L. Search for Related Content PubMed PubMed Citation Articles by Kassel, K. M. Articles by Toews, M. L.

Modulation of epidermal growth factor receptor binding to human airway smooth muscle cells by glucocorticoids and β₂-adrenergic receptor agonists

Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska

Submitted 15 August 2008 ; accepted in final form 29 January 2009

EGF receptors (EGFRs) are increased in airway smooth muscle in asthma, which may contribute to both their hyperproliferation and hypercontractility. Lysophosphatidic acid (LPA) is a candidate pathological agent in asthma and other airway diseases, and LPA upregulates EGFRs in human airway smooth muscle (HASM) cells. We tested whether therapeutic glucocorticoids and/or β₂-adrenergic receptor (β₂AR) agonists also alter EGFR binding in HASM cells. Exposure to glucocorticoids for 24 h induced a twofold increase in EGFR binding similar to that with LPA; fluticasone was markedly more potent than dexamethasone. The increase in EGFR binding by glucocorticoids required 24-h exposure, consistent with transcription-mediated effects. Although the increase in EGFR binding was blocked by the protein synthesis inhibitor cycloheximide for LPA, fluticasone, and dexamethasone, only LPA induced a significant increase in EGFR protein expression detected by immunoblotting. In contrast to the increased binding induced by the glucocorticoids, the β₂AR agonists isoproterenol, albuterol, and salmeterol all induced a decrease in EGFR binding. β₂AR agonist effects were multiphasic, with an initial decline at 2–4 h that reversed by 6 h and a second, somewhat greater decrease by 18–24 h. In cells pretreated with glucocorticoids, the decreases in EGFR binding by subsequent β₂AR treatment were not statistically significant; glucocorticoid upregulation of EGFRs also prevented further increases by LPA. Similar increases by glucocorticoids and decreases by β₂AR agonists were found in HFL-1 human lung fibroblasts. These complex and opposing effects of clinically relevant glucocorticoids and β₂AR agonists on airway mesenchymal cell EGFRs likely contribute to their overall therapeutic profile in the diseased airway.

lysophosphatidic acid; lung fibroblasts; combination therapy