scholarly journals Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in Human Lung Microvascular Endothelial Cells Controls Oxidative Stress, Reactive Oxygen-Mediated Cell Signaling and Inflammatory Responses

2020 ◽  
Vol 11 ◽  
Author(s):  
Maha Khalaf ◽  
Toby Scott-Ward ◽  
Adam Causer ◽  
Zoe Saynor ◽  
Anthony Shepherd ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cystic Fibrosis ◽  
Endothelial Cells ◽  
Cell Signaling ◽  
Human Lung ◽  
Inflammatory Responses ◽  
Microvascular Endothelial Cells ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cystic Fibrosis Transmembrane

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 Infection by Toxoplasma gondii, a severe parasite in neonates and AIDS patients, causes impaired anion secretion in airway epithelia

2015 ◽  
Vol 112 (14) ◽  
pp. 4435-4440 ◽  
Author(s):  
Hong-Mei Guo ◽  
Jiang-Mei Gao ◽  
Yu-Li Luo ◽  
Yan-Zi Wen ◽  
Yi-Lin Zhang ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Toxoplasma Gondii ◽  
Infected Mouse ◽  
Inflammatory Responses ◽  
Short Circuit ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Airway Epithelia ◽  
Anion Secretion ◽  
Cystic Fibrosis Transmembrane

The airway epithelia initiate and modulate the inflammatory responses to various pathogens. The cystic fibrosis transmembrane conductance regulator-mediated Cl− secretion system plays a key role in mucociliary clearance of inhaled pathogens. We have explored the effects of Toxoplasma gondii, an opportunistic intracellular protozoan parasite, on Cl− secretion of the mouse tracheal epithelia. In this study, ATP-induced Cl− secretion indicated the presence of a biphasic short-circuit current (Isc) response, which was mediated by a Ca2+-activated Cl− channel (CaCC) and the cystic fibrosis transmembrane conductance regulator. However, the ATP-evoked Cl− secretion in T. gondii-infected mouse tracheal epithelia and the elevation of [Ca2+]i in T. gondii-infected human airway epithelial cells were suppressed. Quantitative reverse transcription–PCR revealed that the mRNA expression level of the P2Y2 receptor (P2Y2-R) increased significantly in T. gondii-infected mouse tracheal cells. This revealed the influence that pathological changes in P2Y2-R had on the downstream signal, suggesting that P2Y2-R was involved in the mechanism underlying T. gondii infection in airways. These results link T. gondii infection as well as other pathogen infections to Cl− secretion, via P2Y2-R, which may provide new insights for the treatment of pneumonia caused by pathogens including T. gondii.

scholarly journals An Intriguing Involvement of Mitochondria in Cystic Fibrosis

2019 ◽  
Vol 8 (11) ◽  
pp. 1890 ◽  
Author(s):  
Favia ◽  
de Bari ◽  
Bobba ◽  
Atlante
Keyword(s):  
Oxidative Stress ◽  
Cystic Fibrosis ◽  
Causative Factor ◽  
Transmembrane Conductance Regulator ◽  
Many Body ◽  
Transmembrane Conductance ◽  
Leading Role ◽  
Elevated Glucose ◽  
Cftr Protein ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis (CF) occurs when the cystic fibrosis transmembrane conductance regulator (CFTR) protein is not synthetized and folded correctly. The CFTR protein helps to maintain the balance of salt and water on many body surfaces, such as the lung surface. When the protein is not working correctly, chloride becomes trapped in cells, then water cannot hydrate the cellular surface and the mucus covering the cells becomes thick and sticky. Furthermore, a defective CFTR appears to produce a redox imbalance in epithelial cells and extracellular fluids and to cause an abnormal generation of reactive oxygen species: as a consequence, oxidative stress has been implicated as a causative factor in the aetiology of the process. Moreover, massive evidences show that defective CFTR gives rise to extracellular GSH level decrease and elevated glucose concentrations in airway surface liquid (ASL), thus encouraging lung infection by pathogens in the CF advancement. Recent research in progress aims to rediscover a possible role of mitochondria in CF. Here the latest new and recent studies on mitochondrial bioenergetics are collected. Surprisingly, they have enabled us to ascertain that mitochondria have a leading role in opposing the high ASL glucose level as well as oxidative stress in CF.

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.

scholarly journals Cigarette Smoke-Induced Acquired Dysfunction of Cystic Fibrosis Transmembrane Conductance Regulator in the Pathogenesis of Chronic Obstructive Pulmonary Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Juan Shi ◽  
Hui Li ◽  
Chao Yuan ◽  
Meihui Luo ◽  
Jun Wei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Obstructive Pulmonary Disease ◽  
Cystic Fibrosis ◽  
Pulmonary Disease ◽  
Cigarette Smoke ◽  
Chronic Obstructive ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Obstructive Pulmonary Disease ◽  
Cystic Fibrosis Transmembrane

Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible. Cigarette smoke and oxidative stress are main etiological risks in COPD. Interestingly, recent studies suggest a considerable overlap between chronic bronchitis (CB) phenotypic COPD and cystic fibrosis (CF), a common fatal hereditary lung disease caused by genetic mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Phenotypically, CF and COPD are associated with an impaired mucociliary clearance and mucus hypersecretion, although they are two distinct entities of unrelated origin. Mechanistically, the cigarette smoke-increased oxidative stress-induced CFTR dysfunction is implicated in COPD. This underscores CFTR in understanding and improving therapies for COPD by altering CFTR function with antioxidant agents and CFTR modulators as a great promising strategy for COPD treatments. Indeed, treatments that restore CFTR function, including mucolytic therapy, antioxidant ROS scavenger, CFTR stimulator (roflumilast), and CFTR potentiator (ivacaftor), have been tested in COPD. This review article is aimed at summarizing the molecular, cellular, and clinical evidence of oxidative stress, particularly the cigarette smoke-increased oxidative stress-impaired CFTR function, as well as signaling pathways of CFTR involved in the pathogenesis of COPD, with a highlight on the therapeutic potential of targeting CFTR for COPD treatment.

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