CFTR is the Primary Known Apical Glutathione Transporter Involved in Cigarette Smoke-induced Adaptive Responses in the Lung

One of the most abundant antioxidants in the lung is glutathione (GSH), a low-molecular-weight thiol, which functions to attenuate both oxidative stress and inflammation. GSH is concentrated in the epithelial lining fluid (ELF) of the lung and can be elevated in response to the increased oxidant burden from cigarette smoke (CS). However, the transporter(s) responsible for the increase in ELF GSH with cigarette smoke is not known. Three candidate apical GSH transporters in the lung are CFTR, BCRP, and MRP2, but their potential roles in ELF GSH transport in response to CS have not been investigated. In vitro, the inhibition of CFTR, BCRP, or MRP2 resulted in decreased GSH efflux in response to cigarette smoke extract. In vivo, mice deficient in CFTR, BCRP, or MRP2 were exposed to either air or acute CS. CFTR-deficient mice had reduced basal and CS-induced GSH in the ELF, whereas BCRP or MRP2 deficiency had no effect on ELF GSH basal or CS-exposed levels. Furthermore, BCRP or MRP2 deficiency had little effect on lung tissue GSH. These data indicate that CFTR is predominantly involved in maintaining basal ELF GSH and increasing ELF GSH in response to CS.