Erythromycin and clarithromycin attenuate cytokine-induced endothelin-1 expression in human bronchial epithelial cells.
Erythromycin and its fourteen-member macrolide analogues have attracted attention for their efficacy in bronchial asthma. However, their mechanisms of action remain unclear. We evaluated the effects of the macrolide antibiotics on endothelin-1 (ET-1) expression in normal and transformed human bronchial epithelial cells, one of the sources of this potent bronchoconstrictor important in the pathogenesis of asthma. Human 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 evaluated. Bronchoepithelial cells were also isolated from the mucosa of asthmatic patients under fibreoptic bronchoscopy, and the modulating effects of the drugs were studied. Erythromycin and clarithromycin uniquely suppressed mRNA levels as well as the release of ET- at therapeutic and non-cytotoxic concentrations (percentage inhibition of ET-1 protein release: 26.4+/-5.22% and 31.2+/-7.45%, respectively, at 10(-6) M). Furthermore, erythromycin and clarithromycin inhibited ET-1 expression in bronchoepithelial cells from patients with chronic, stable asthma. A glucocorticosteroid, dexamethasone, also inhibited ET-1 expression. In contrast, theophylline, salbutamol and FK506 had no effect on ET-1 production. Our findings demonstrated that these fourteen-member macrolide antibiotics had an inhibitory effect on endothelin-1 expression in human bronchial epithelial cells. Moreover, this new mode of action may have some relevance to their clinical efficacy in bronchial asthma.
Takizawa
H
H
Dept of Medicine & Physical Therapy, University of Tokyo, School of Medicine, Japan.
Desaki
M
M
Ohtoshi
T
T
Kawasaki
S
S
Kohyama
T
T
Sato
M
M
Nakajima
J
J
Yanagisawa
M
M
Ito
K
K
D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001249:Asthma / Q000276:immunology; D001980:Bronchi / Q000187:drug effects*; D002461:Cell Line, Transformed; D017291:Clarithromycin / Q000494:pharmacology*; D046508:Culture Techniques; D016207:Cytokines / Q000502:physiology*; D019332:Endothelin-1 / Q000235:genetics*; D004847:Epithelial Cells / Q000187:drug effects*; D004917:Erythromycin / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000187:drug effects
D000900:Anti-Bacterial Agents; D016207:Cytokines; D019332:Endothelin-1; D012333:RNA, Messenger; D004917:Erythromycin; D017291:Clarithromycin