CFTR and lung homeostasis

Collawn, James F.; Matalon, Sadis

doi:10.1152/ajplung.00326.2014

Cited by 77 publications

(59 citation statements)

References 80 publications

(93 reference statements)

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“…6 CF is a monogenic disorder caused by a mutation in the cystic fibrosis transmembrane regulator (CFTR), a protein that is important to regulation of airway hydration. 44,45 CFTR dysfunction initiates a cascade of events that include reduced MCC, airway obstruction, persistent infection, and chronic inflammation. [46][47][48][49] COPD is triggered by continous exposure to environmental toxins, primarily cigarette smoke, that cause chronic inflammation, goblet cell metaplasia, mucus accumulation, and airway obstruction.…”

Section: Mucus In Individuals With Lung Diseasementioning

confidence: 99%

The Mucus Barrier to Inhaled Gene Therapy

et al. 2016

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Recent evidence suggests that the airway mucus gel layer may be impermeable to the viral and synthetic gene vectors used in past inhaled gene therapy clinical trials for diseases like cystic fibrosis. These findings support the logic that inhaled gene vectors that are incapable of penetrating the mucus barrier are unlikely to provide meaningful benefit to patients. In this review, we discuss the biochemical and biophysical features of mucus that contribute its barrier function, and how these barrier properties may be reinforced in patients with lung disease. We next review biophysical techniques used to assess the potential ability of gene vectors to penetrate airway mucus. Finally, we provide new data suggesting that fresh human airway mucus should be used to test the penetration rates of gene vectors. The physiological barrier properties of spontaneously expectorated CF sputum remained intact up to 24 hours after collection when refrigerated at 4 °C. Conversely, the barrier properties were significantly altered after freezing and thawing of sputum samples. Gene vectors capable of overcoming the airway mucus barrier hold promise as a means to provide the widespread gene transfer throughout the airway epithelium required to achieve meaningful patient outcomes in inhaled gene therapy clinical trials.

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Section: Mucus In Individuals With Lung Diseasementioning

confidence: 99%

The Mucus Barrier to Inhaled Gene Therapy

et al. 2016

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“…Reduced pathogen clearance facilitates infection that induces neutrophilic inflammation, leading to progressive epithelial damage within the conducting airways [16][17][18][19]. Over time, a recurrent cycle of intense inflammation, epithelial injury and airway remodeling produce irrevocable damage that dramatically compromises lung function [20][21][22]. Mounting evidence from in vitro studies and animal models of CF indicate that CFTR malfunction appears to alter the innate immune response of the airways leading to increased release of proinflammatory mediators evoking an amplified, yet less effective inflammatory reaction that is unable to eliminate airway pathogens [17,18].…”

Section: Airway Inflammation and Epithelial Damagementioning

confidence: 99%

CFTR Involvement in Cell Migration and Epithelial Restitution

O’Grady¹

2017

Progress in Understanding Cystic Fibrosis

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Over the past decade, research has shown that cystic fibrosis transmembrane conductance regulator (CFTR) plays an important role in epithelial cell migration and wound healing. Experiments with airway epithelium, ovarian epithelial cells, placental epithelium and epidermal keratinocytes demonstrated that CFTR function is necessary to achieve maximum migration rates during restitution and in certain cancer cells, CFTR activity contributes to tumor cell invasion. Multiple mechanisms appear to underlie the motility-promoting actions of CFTR, and although many details remain to be established, our present understanding indicates that processes such as electrotaxis (galvanotaxis), integrin-mediated cell adhesion and lamellipodia protrusion are dependent on normal CFTR function. In this chapter, the role of CFTR in epithelial cell migration and its implications in cystic fibrosis (CF) will be reviewed with emphasis on the underlying mechanisms that may explain observations made in various epithelial tissues, particularly in airways. Ultimately, a better understanding of CFTR involvement in epithelial repair may lead to new therapeutic approaches to improve barrier function and reduce airway infection and inflammation associated with CF.

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“…Aldehydes and heavy metals have been shown to have a number of cytotoxic effects on epithelia, including adduct formation to DNA (32,140,154). Additionally, tobacco smoke, as well as aldehydes, cadmium, and oxidative stress, also affect plasma membrane proteins such as the cystic fibrosis transmembrane conductance regulator (CFTR) (25,33,70,137), which is required for fluid secretion in the lung (35,60). In contrast, e-liquids (the flavored liquids that are heated to form the E-Cig vapor) are thought to be much simpler and ostensibly contain nicotine (ϳ6 -18 mg/ml) in a liquid vehicle (typically propylene glycol and/or glycerin), along with sweeteners and flavorings (65).…”

Section: Tissue/cell Type Effectsmentioning

confidence: 99%

Will chronic e-cigarette use cause lung disease?

Rowell

Tarran

2015

American Journal of Physiology-Lung Cellular and Molecular Phys

103

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Chronic tobacco smoking is a major cause of preventable morbidity and mortality worldwide. In the lung, tobacco smoking increases the risk of lung cancer, and also causes chronic obstructive pulmonary disease (COPD), which encompasses both emphysema and chronic bronchitis. E-cigarettes (E-Cigs), or electronic nicotine delivery systems, were developed over a decade ago and are designed to deliver nicotine without combusting tobacco. Although tobacco smoking has declined since the 1950s, E-Cig usage has increased, attracting both former tobacco smokers and never smokers. E-Cig liquids (e-liquids) contain nicotine in a glycerol/propylene glycol vehicle with flavorings, which are vaporized and inhaled. To date, neither E-Cig devices, nor e-liquids, are regulated by the Food and Drug Administration (FDA). The FDA has proposed a deeming rule, which aims to initiate legislation to regulate E-Cigs, but the timeline to take effect is uncertain. Proponents of E-Cigs say that they are safe and should not be regulated. Opposition is varied, with some opponents proposing that E-Cig usage will introduce a new generation to nicotine addiction, reversing the decline seen with tobacco smoking, or that E-Cigs generally may not be safe and will trigger diseases like tobacco. In this review, we shall discuss what is known about the effects of E-Cigs on the mammalian lung and isolated lung cells in vitro. We hope that collating this data will help illustrate gaps in the knowledge of this burgeoning field, directing researchers toward answering whether or not E-Cigs are capable of causing disease.

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CFTR and lung homeostasis

Cited by 77 publications

References 80 publications

The Mucus Barrier to Inhaled Gene Therapy

The Mucus Barrier to Inhaled Gene Therapy

CFTR Involvement in Cell Migration and Epithelial Restitution

Will chronic e-cigarette use cause lung disease?

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