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1 Department of Medicine, National Jewish Medical and Research Center, and 3 Department of Medicine and Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado 80206; and 2 Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio 44106
Recent studies
suggest that the cystic fibrosis (CF) transmembrane conductance
regulator (CFTR) protein modulates epithelial reduced glutathione (GSH)
transport and when defective creates an antioxidant imbalance. To test
whether the CFTR protein modulates lung antioxidant defenses in vivo,
epithelial lining fluid (ELF) and lung tissue from CFTR knockout
(CFTR-KO) and wild-type (WT) mice were compared for GSH content and the
activities of glutathione reductase, glutathione peroxidase, and
-glutamyltransferase. In the CFTR-KO mice, the ELF concentration of
GSH was decreased (51%) compared with that in WT mice. The
concentration of GSH in the lung tissue of CFTR-KO mice, however, was
not significantly different from that in WT mice. The activities of
glutathione reductase and glutathione peroxidase in the lung tissue of
CFTR-KO mice were significantly increased compared with those in WT
mice (48 and 28%, respectively). Tissue lipid and DNA oxidation were evaluated by measurement of thiobarbituric acid-reactive substances and
8-hydroxy-2'-deoxyguanosine, respectively. The levels of thiobarbituric acid-reactive substances and 8-hydroxy-2'-deoxyguanosine in the lung
tissue of CFTR-KO mice were significantly increased compared with those
in WT mice. These data support our hypothesis that a mutation in the
CFTR gene can affect the antioxidant defenses in the lung and may
contribute to the exaggerated inflammatory response observed in CF.
epithelial lining fluid; glutathione; oxidative stress
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