Suppression of Adenosine-Activated Chloride Transport by Ethanol in Airway Epithelia

Raju, Sammeta V.; Wang, Guoshun

doi:10.1371/journal.pone.0032112

Cited by 9 publications

(9 citation statements)

References 47 publications

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“…For example, studies in individuals who harbor partially functional CFTR mutations demonstrate that CFTR abnormalities greatly increase the risk of recurrent idiopathic pancreatitis (34). Given that at least 15% of patients with idiopathic pancreatitis are heterozygous for CFTR mutations (3,35), and many causative CFTR mutations confer only modest dysfunction, it seems possible that CFTR dysfunction at the levels we observed is sufficient to increase the risk of both pulmonary and extrapulmonary disease, particularly when compounded by additional insults, such as alcohol, which has also been associated with CFTR dysfunction (36).…”

Section: Discussionmentioning

confidence: 73%

Cigarette Smoke Induces Systemic Defects in Cystic Fibrosis Transmembrane Conductance Regulator Function

Raju

Jackson

Courville³

et al. 2013

Am J Respir Crit Care Med

173

201

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Rationale: Several extrapulmonary disorders have been linked to cigarette smoking. Smoking is reported to cause cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in the airway, and is also associated with pancreatitis, male infertility, and cachexia, features characteristic of cystic fibrosis and suggestive of an etiological role for CFTR. Objectives: To study the effect of cigarette smoke on extrapulmonary CFTR function. Methods: Demographics, spirometry, exercise tolerance, symptom questionnaires, CFTR genetics, and sweat chloride analysis were obtained in smokers with and without chronic obstructive pulmonary disease (COPD). CFTR activity was measured by nasal potential difference in mice and by Ussing chamber electrophysiology in vitro. Serum acrolein levels were estimated with mass spectroscopy. Measurements and Main Results: Healthy smokers (29.45 6 13.90 mEq), smokers with COPD (31.89 6 13.9 mEq), and former smokers with COPD (25.07 6 10.92 mEq) had elevated sweat chloride levels compared with normal control subjects (14.5 6 7.77 mEq), indicating reduced CFTR activity in a nonrespiratory organ. Intestinal current measurements also demonstrated a 65% decrease in CFTR function in smokers compared with never smokers. CFTR activity was decreased by 68% in normal human bronchial epithelial cells exposed to plasma from smokers, suggesting that one or more circulating agents could confer CFTR dysfunction. Cigarette smokeexposed mice had decreased CFTR activity in intestinal epithelium (84.3 and 45%, after 5 and 17 wk, respectively). Acrolein, a component of cigarette smoke, was higher in smokers, blocked CFTR by inhibiting channel gating, and was attenuated by antioxidant N-acetylcysteine, a known scavenger of acrolein. Conclusions: Smoking causes systemic CFTR dysfunction. Acrolein present in cigarette smoke mediates CFTR defects in extrapulmonary tissues in smokers.

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Section: Discussionmentioning

confidence: 73%

Cigarette Smoke Induces Systemic Defects in Cystic Fibrosis Transmembrane Conductance Regulator Function

Raju

Jackson

Courville³

et al. 2013

Am J Respir Crit Care Med

173

201

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“…26 In addition, Raju et al demonstrated that basolateral ethanol exposure (0, 25, 50 and 100 mM) for 24 hours reduced epithelial short-circuit currents (I SC ) in a dose-dependent manner. 27 …”

Section: Discussionmentioning

confidence: 99%

Cystic fibrosis transmembrane conductance regulator activation by the solvent ethanol: implications for topical drug delivery

Cho

Skinner

Zhang

et al. 2015

Int Forum Allergy Rhinol

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Background Decreased CFTR-mediated chloride (Cl) secretion across mucosal surfaces contributes to the development of airway disease by depleting airway surface liquid, increasing mucus viscosity and adhesion, and consequently hindering mucociliary clearance. We serendipitously discovered during testing of drugs solubilized in low concentrations ethanol (0.25%, 43mM) that the control vehicle produced robust activation of CFTR-mediated Cl− transport. The objective of the current study is to investigate low concentrations ethanol for effects on Cl− secretion and ciliary beat frequency (CBF). Methods Wild type (WT) and transgenic CFTR−/− primary murine nasoseptal epithelial (MNSE) and WT and F508del/F508del human sinonasal epithelial (HSNE) cultures were subjected to transepithelial ion transport measurements using pharmacologic manipulation in Ussing chambers. CBF activation was also monitored. Murine nasal potential difference (NPD) was measured in vivo. Results Ussing chamber tracings revealed ethanol activated CFTR-mediated Cl transport in a dose-dependent fashion in WT MNSE (n=4, p<0.05) and HSNE (n=4, p<0.05). Ethanol also significantly increased CBF (fold-change) in WT MNSE cultures in a dose dependent fashion [PBS, 1.33+/−0.04; 0.25% Ethanol, 1.37+/−0.09; 0.5% Ethanol, 1.53+/−0.06 (p<0.05), 1% Ethanol, 1.62+/−0.1 (p<0.05)]. Lack of stimulation in CFTR−/− and F508del/F508del cultures indicated activity was dependent on the presence of intact functional CFTR. Ethanol perfusion (0.5%) resulted in a significant −3.5mV mean NPD polarization when compared to control solution (p<0.05). Conclusion The observation that brief exposure of ethanol stimulated Cl− secretion via CFTR-mediated pathways indicates possible use as topical aerosol delivered alone or in combination with other CFTR activators for diseases of dysfunctional MCC in CRS.

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“…There is no standard in vitro model of the alveolar epithelial barrier to study drug transport, pharmacokinetics and bioreactivity; for example many in vitro studies utilise the A549 adenocarcinoma cell line as a substitute for primary human alveolar epithelial type II cells [ 24 – 26 ], whilst others utilise the Calu-3 human bronchial epithelial cell line, also derived from a pulmonary adenocarcinoma, to investigate changes in barrier function of large airway epithelium [ 27 , 28 ]. We believe it is also relevant to use cell lines derived from normal lung cells and primary cells [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Differential bioreactivity of neutral, cationic and anionic polystyrene nanoparticles with cells from the human alveolar compartment: robust response of alveolar type 1 epithelial cells

2015

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BackgroundEngineered nanoparticles (NP) are being developed for inhaled drug delivery. This route is non-invasive and the major target; alveolar epithelium provides a large surface area for drug administration and absorption, without first pass metabolism. Understanding the interaction between NPs and target cells is crucial for safe and effective NP-based drug delivery. We explored the differential effect of neutral, cationic and anionic polystyrene latex NPs on the target cells of the human alveolus, using primary human alveolar macrophages (MAC) and primary human alveolar type 2 (AT2) epithelial cells and a unique human alveolar epithelial type I-like cell (TT1). We hypothesized that the bioreactivity of the NPs would relate to their surface chemistry, charge and size as well as the functional role of their interacting cells in vivo.MethodsAmine- (ANP) and carboxyl- surface modified (CNP) and unmodified (UNP) polystyrene NPs, 50 and 100 nm in diameter, were studied. Cells were exposed to 1–100 μg/ml (1.25-125 μg/cm2; 0 μg/ml control) NP for 4 and 24 h at 37 °C with or without the antioxidant, N-acetyl cysteine (NAC). Cells were assessed for cell viability, reactive oxygen species (ROS), oxidised glutathione (GSSG/GSH ratio), mitochondrial integrity, cell morphology and particle uptake (using electron microscopy and laser scanning confocal microscopy).ResultsANP-induced cell death occurred in all cell types, inducing increased oxidative stress, mitochondrial disruption and release of cytochrome C, indicating apoptotic cell death. UNP and CNP exhibited little cytotoxicity or mitochondrial damage, although they induced ROS in AT2 and MACs. Addition of NAC reduced epithelial cell ROS, but not MAC ROS, for up to 4 h. TT1 and MAC cells internalised all NP formats, whereas only a small fraction of AT2 cells internalized ANP (not UNP or CNP). TT1 cells were the most resistant to the effects of UNP and CNP.ConclusionANP induced marked oxidative damage and cell death via apoptosis in all cell types, while UNP and CNP exhibited low cytotoxicity via oxidative stress. MAC and TT1 cell models show strong particle-internalization compared to the AT2 cell model, reflecting their cell function in vivo. The 50 nm NPs induced a higher bioreactivity in epithelial cells, whereas the 100 nm NPs show a stronger effect on phagocytic cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-015-0091-7) contains supplementary material, which is available to authorized users.

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Suppression of Adenosine-Activated Chloride Transport by Ethanol in Airway Epithelia

Cited by 9 publications

References 47 publications

Cigarette Smoke Induces Systemic Defects in Cystic Fibrosis Transmembrane Conductance Regulator Function

Cigarette Smoke Induces Systemic Defects in Cystic Fibrosis Transmembrane Conductance Regulator Function

Cystic fibrosis transmembrane conductance regulator activation by the solvent ethanol: implications for topical drug delivery

Differential bioreactivity of neutral, cationic and anionic polystyrene nanoparticles with cells from the human alveolar compartment: robust response of alveolar type 1 epithelial cells

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