Azithromycin and ciprofloxacin have a chloroquine-like effect on respiratory epithelial cells

Vojo Deretic; Graham S Timmins

Genetic polymorphisms 49 associated with elevated profibrotic mediator TGF-b are key disease modifiers in CF, with elevated TGF-b increasing disease severity [50] [51] [52] [53] . We have reported that TGF-β generated by CF respiratory epithelial cells is increased compared to normal cells and that treatment with the weak base CQ can correct TGF-β release 27, 33 . When AZT was tested, it too reduced TGF-β (Fig. 4A) . We have reported that the elevated TGF-β in CF cells is caused by increased furin activity in the intracellular organelles of CF respiratory epithelial cells 27 . Hence, we tested whether AZT affected the furin inbalance. When CF cells were incubated with 100 µM AZT, production of active furin was normalized in CF cells, on par with CQ treatment and on level with the CFTR-corrected S9 cells (Fig. 4B) . These results indicate that correcting organellar pH with AZT normalizes the excessive processing and activation of furin in CF cells. In summary, AZT benefits in CF that cannot be explained by its direct antibiotic activity are due to its physical-chemical action as a weak base, normalizing organellar function and cell-autonomous responses of CF respiratory epithelial cells.