Hypertonic saline increases lung epithelial lining fluid glutathione and thiocyanate: two protective CFTR-dependent thiols against oxidative injury.
BACKGROUND
Cystic fibrosis is a debilitating lung disease due to mutations in the cystic fibrosis transmembrane conductance regulator protein (CFTR) and is associated with chronic infections resulting in elevated myeloperoxidase activity and generation of hypochlorous acid (HOCl). CFTR mutations lead to decreased levels of glutathione (GSH) and thiocyanate (SCN) in the epithelial lining fluid (ELF). Hypertonic saline is used to improve lung function however the mechanism is uncertain.


METHODS
In the present study, the effect of GSH and SCN on HOCl-mediated cell injury and their changes in the ELF after hypertonic saline nebulization in wild type (WT) and CFTR KO mice was examined. CFTR sufficient and deficient lung cells were assessed for GSH, SCN and corresponding sensitivity towards HOCl-mediated injury, in vitro.


RESULTS
CFTR (-) cells had lower extracellular levels of both GSH and SCN and were more sensitive to HOCl-mediated injury. In vivo, hypertonic saline increased ELF GSH in the WT and to a lesser extent in the CFTR KO mice but only SCN in the WT ELF. Finally, potential protective effects of GSH and SCN at concentrations found in the ELF against HOCl toxicity were examined in vitro.


CONCLUSIONS
While the concentrations of GSH and SCN associated with the WT ELF protect against HOCl toxicity, those found in the CFTR KO mice were less sufficient to inhibit cell injury. These data suggests that CFTR has important roles in exporting GSH and SCN which are protective against oxidants and that hypertonic saline treatment may have beneficial effects by increasing their levels in the lung.
Gould
Neal S
NS
Department of Medicine, University of Colorado Denver, Aurora, CO 80045 USA.
Gauthier
Steve
S
Kariya
Chirag T
CT
Min
Elysia
E
Huang
Jie
J
Brian
Day J
DJ
D055371:Acute Lung Injury / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D000818:Animals; D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018181:Mice, Inbred CFTR; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010084:Oxidation-Reduction / Q000187:drug effects; D020011:Protective Agents / Q000627:therapeutic use; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*; D012462:Saline Solution, Hypertonic / Q000627:therapeutic use*; D013438:Sulfhydryl Compounds / Q000502:physiology*; D013861:Thiocyanates / Q000378:metabolism*
C505032:CFTR protein, human; D020011:Protective Agents; D012462:Saline Solution, Hypertonic; D013438:Sulfhydryl Compounds; D013861:Thiocyanates; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005978:Glutathione; C031760:thiocyanate
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