Long-term azithromycin in cystic fibrosis: another possible mechanism of action?
Azithromycin is used for the treatment of cystic fibrosis lung disease, although its mechanisms of action are not completely understood. Besides its antiinflammatory and antimicrobial activities, one possibility could be the overexpression induction of the multidrug resistance-associated protein (MRP), which could affect chloride transport, thus overcoming the ion transport defect of cystic fibrosis. Seven patients were evaluated before and after 4 weeks of azithromycin treatment (500 mg once daily). Ion transport was studied in vivo by measuring nasal potential difference (NPD). MRP mRNA expression was studied in nasal cells by an internal standard-based semiquantitative RT-PCR assay. NPD was consistent with cystic fibrosis before treatment. After azithromycin treatment, sodium transport was still impaired, whereas a significant increase in chloride conductance was observed (p = 0.03). A significant direct correlation was found between MRP mRNA expression levels and NPD chloride response after azithromycin treatment (p = 0.04, r = 0.78). In conclusion, azithromycin may induce MRP overexpression and restore chloride conductance in the airways of cystic fibrosis patients. These findings suggest a new potential role of azithromycin in the treatment of cystic fibrosis pulmonary disease, i.e. the possibility to upregulate proteins whose function may, at least in part, compensate for the basic defect of cystic fibrosis.
Pradal
U
U
Cystic Fibrosis Center, Azienda Ospedaliera di Verona, Verona, Italy. ugo.pradal@azosp.vr.it
Delmarco
A
A
Morganti
M
M
Cipolli
M
M
Mini
E
E
Cazzola
G
G
D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D017963:Azithromycin / Q000008:administration & dosage*; D003550:Cystic Fibrosis / Q000175:diagnosis / Q000188:drug therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004269:DNA, Bacterial / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D008134:Long-Term Care; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects* / Q000378:metabolism; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism; D011336:Probability; D011446:Prospective Studies; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D016896:Treatment Outcome
D000900:Anti-Bacterial Agents; D017963:Azithromycin; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004269:DNA, Bacterial; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; C505032:CFTR protein, human