scholarly journals Role for Cystic Fibrosis Transmembrane Conductance Regulator Protein in a Glutathione Response to Bronchopulmonary Pseudomonas Infection

2004 ◽  
Vol 72 (4) ◽  
pp. 2045-2051 ◽  
Author(s):  
Brian J. Day ◽  
Anna M. van Heeckeren ◽  
Elysia Min ◽  
Leonard W. Velsor
Keyword(s):  
Oxidative Stress ◽  
Cystic Fibrosis ◽  
Lung Tissue ◽  
Lung Infection ◽  
Transmembrane Conductance Regulator ◽  
Wild Type ◽  
Transmembrane Conductance ◽  
Twofold Increase ◽  
Regulator Protein ◽  
Cystic Fibrosis Transmembrane

ABSTRACT The lung maintains an elevated level of glutathione (GSH) in epithelial lining fluid (ELF) compared to serum. The mechanism(s) by which the lung maintains high levels of ELF GSH and factors that modulate them are largely unexplored. We hypothesized that lung cystic fibrosis transmembrane conductance regulator protein (CFTR) modulates GSH efflux in response to extracellular stress, which occurs with lung infections. Mice were challenged intratracheally with Pseudomonas aeruginosa, and on the third day of infection bronchoalveolar lavage fluid was obtained and analyzed for cytokines and antioxidants. Lung tissue antioxidants and enzyme activities were also assessed. P. aeruginosa lung infection increased levels of inflammatory cytokines and neutrophils in the ELF. This corresponded with a marked threefold increase in GSH and a twofold increase in urate levels in the ELF of P. aeruginosa-infected wild-type mice. A twofold increase in urate levels was also observed among lung tissue antioxidants of P. aeruginosa-infected wild-type mice. There were no changes in markers of lung oxidative stress associated with the P. aeruginosa lung infection. In contrast with wild-type mice, the CFTR knockout mice lacked a significant increase in ELF GSH when challenged with P. aeruginosa, and this correlated with a decrease in the ratio of reduced to oxidized GSH in the ELF, a marker of oxidative stress. These data would suggest that the lung adapts to infectious agents with elevated ELF GSH and urate. Individuals with lung diseases associated with altered antioxidant transport, such as cystic fibrosis, might lack the ability to adapt to the infection and present with a more severe inflammatory response.

Glutathione permeability of CFTR

1998 ◽  
Vol 275 (1) ◽  
pp. C323-C326 ◽  
Author(s):  
Paul Linsdell ◽  
John W. Hanrahan
Keyword(s):  
Oxidative Stress ◽  
Cystic Fibrosis ◽  
Ion Channel ◽  
Airway Epithelial Cells ◽  
Transmembrane Conductance Regulator ◽  
Airway Epithelial ◽  
Transmembrane Conductance ◽  
High Concentrations ◽  
Cystic Fibrosis Transmembrane ◽  
Glutathione Transport

The cystic fibrosis transmembrane conductance regulator (CFTR) forms an ion channel that is permeable both to Cl− and to larger organic anions. Here we show, using macroscopic current recording from excised membrane patches, that the anionic antioxidant tripeptide glutathione is permeant in the CFTR channel. This permeability may account for the high concentrations of glutathione that have been measured in the surface fluid that coats airway epithelial cells. Furthermore, loss of this pathway for glutathione transport may contribute to the reduced levels of glutathione observed in airway surface fluid of cystic fibrosis patients, which has been suggested to contribute to the oxidative stress observed in the lung in cystic fibrosis. We suggest that release of glutathione into airway surface fluid may be a novel function of CFTR.

scholarly journals Carbon monoxide-releasing molecules inhibit the cystic fibrosis transmembrane conductance regulator Cl− channel

2020 ◽  
Vol 319 (6) ◽  
pp. L997-L1009
Author(s):  
Mayuree Rodrat ◽  
Walailak Jantarajit ◽  
Demi R. S. Ng ◽  
Bartholomew S. J. Harvey ◽  
Jia Liu ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Carbon Monoxide ◽  
Current Flow ◽  
Open Channels ◽  
Transmembrane Conductance Regulator ◽  
Channel Activity ◽  
Wild Type ◽  
Transmembrane Conductance ◽  
Flow Through ◽  
Cystic Fibrosis Transmembrane

The gasotransmitter carbon monoxide (CO) regulates fluid and electrolyte movements across epithelial tissues. However, its action on anion channels is incompletely understood. Here, we investigate the direct action of CO on the cystic fibrosis transmembrane conductance regulator (CFTR) by applying CO-releasing molecules (CO-RMs) to the intracellular side of excised inside-out membrane patches from cells heterologously expressing wild-type human CFTR. Addition of increasing concentrations of tricarbonyldichlororuthenium(II) dimer (CORM-2) (1–300 μM) inhibited CFTR channel activity, whereas the control RuCl3 (100 μM) was without effect. CORM-2 predominantly inhibited CFTR by decreasing the frequency of channel openings and, hence, open probability ( Po). But, it also reduced current flow through open channels with very fast kinetics, particularly at elevated concentrations. By contrast, the chemically distinct CO-releasing molecule CORM-3 inhibited CFTR by decreasing Po without altering current flow through open channels. Neither depolarizing the membrane voltage nor raising the ATP concentration on the intracellular side of the membrane affected CFTR inhibition by CORM-2. Interestingly, CFTR inhibition by CORM-2, but not by CFTRinh-172, was prevented by prior enhancement of channel activity by the clinically approved CFTR potentiator ivacaftor. Similarly, when added after CORM-2, ivacaftor completely relieved CFTR inhibition. In conclusion, CORM-2 has complex effects on wild-type human CFTR consistent with allosteric inhibition and open-channel blockade. Inhibition of CFTR by CO-releasing molecules suggests that CO regulates CFTR activity and that the gasotransmitter has tissue-specific effects on epithelial ion transport. The action of ivacaftor on CFTR Cl− channels inhibited by CO potentially expands the drug’s clinical utility.

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