ERYTHROMYCIN AND CLARITHROMYCIN ATTENUATE CYTOKINE-INDUCED ENDOTHELIN-1 EXPRESSION IN HUMAN BRONCHIAL EPITHELIAL-CELLS

Erythromycin and its fourteen-member macrolide analogues have attracte d attention for their efficacy in bronchial asthma, However, their mec hanisms of action remain unclear. We evaluated the effects of the macr olide antibiotics on endothelin-1 (ET-1) expression in normal and tran sformed human bronchial epithelial cells, one of the sources of this p otent bronchoconstrictor important in the pathogenesis of asthma, Huma n bronchial epithelial cells were obtained from the resected bronchi, and the effect of several antimicrobial and antiasthmatic drugs on the production and messenger ribonucleic acid (mRNA) levels of ET-1 was e valuated. Bronchoepithelial cells were also isolated from the mucosa o f asthmatic patients under fibreoptic bronchoscopy, and the modulating effects of the drugs were studied. Erythromycin and clarithromycin un iquely suppressed mRNA levels as well as the release of ET-1 at therap eutic and non-cytotoxic concentrations (percentage inhibition of ET-1 protein release: 26.4+/-5.22% and 31.2+/-17.45%, respectively, at 10(- 6) M), Furthermore, erythromycin and clarithromycin inhibited ET-1 exp ression in bronchoepithelial cells from patients with chronic, stable asthma, A glucocorticosteroid, dexamethasone, also inhibited ET-1 expr ession. In contrast, theophylline, salbutamol and FK506 had no effect on ET-1 production. Our findings demonstrated that these fourteen-memb er macrolide antibiotics had an inhibitory effect on endothelin-1 expr ession in human bronchial epithelial cells. Moreover, this new mode of action may have some relevance 10 their clinical efficacy in bronchia l asthma.