DOWN-REGULATION OF THE EXPRESSION OF INTERCELLULAR-ADHESION MOLECULE (ICAM)-1 ON BRONCHIAL EPITHELIAL-CELLS BY FENOTEROL, A BETA(2)-ADRENOCEPTOR AGONIST

Inflammatory airway disorders, such as asthma and chronic bronchitis, are characterized by overexpression of adhesion molecules on airway ep ithelial and endothelial cells. This phenomenon is associated with inc reased adherence and activation of polymorphonuclear leukocytes (PMNs) . With the knowledge that beta(2)-adrenoceptor agonists demonstrate so me anti-inflammatory activity in vitro, the present study was designed to evaluate whether fenoterol could interfere with adhesion molecule expression on airway epithelium. Human bronchial epithelial cells (HBE Cs), obtained by protease digestion from surgically resected bronchi, were stimulated with human recombinant interferon-gamma (rh IFN-gamma) in the presence of (a) fenoterol (10(-12)-10(-5) M); (b) dexamethason e (10(-12)-10(-5) M); and (c) fenoterol and dexamethasone. Because des ensitization after high-dose exposure to agonists has been described f or many membrane-associated receptors, in additional sets of experimen ts HBECs were preexposed to fenoterol and, as control, to dexamethason e for 8 hr, then washed and stimulated with rh IFN-gamma in the presen ce of fresh drugs. The cells were harvested after 24-hr culture and st ained by specific monoclonal antibodies. The intensity of intercellula r adhesion molecule-1 (ICAM-1) expression was then measured by flow cy tometry analysis and expressed as mean fluorescence channel (mfc). The significant increase in ICAM-1 expression on HBECs induced by rh IFN- gamma was inhibited, in a dose-dependent manner, by the two drugs, but fenoterol was more efficient than dexamethasone at all of the concent rations tested (p < 0.05; all comparisons). In addition, the inhibitor y activity of fenoterol was not enhanced by the simultaneous presence of dexamethasone in rh IFN-gamma-stimulated HBEC cultures (p > 0.05, a ll comparisons). Finally, preexposure to fenoterol or to dexamethasone did not induce any modification of the inhibitory effect of the two d rugs on ICAM-1 expression (p > 0.05, all comparisons). These results s uggest that clinical efficacy of fenoterol in patients with obstructiv e lung disease may include downregulation of adhesion molecule express ion on airway epithelial cells.