The Relationship of Mucus Concentration (Hydration) to Mucus Osmotic Pressure and Transport in Chronic Bronchitis

Anderson, Wayne H.; Coakley, Raymond D.; Button, Brian; Henderson, Ashley G.; Zeman, Kirby L.; Alexis, Neil E.; Peden, David B.; Lazarowski, Eduardo R.; Davis, C. William; Summer, Bailey,; Fuller, Fred; Almond, Martha; Qaqish, Bahjat F.; Bordonali, Elena; Rubinstein, Michael; Bennett, William D.; Kesımer, Mehmet; Boucher, Richard C.

doi:10.1164/rccm.201412-2230oc

Cited by 135 publications

(173 citation statements)

References 54 publications

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“…Our studies show that exposure to IFN-␥ causes inhibition of hypotonic stress-induced ATP release by ϳ78%, which would impair proper mucociliary clearance. Our data fit well with data from a recent publication showing that smokers and patients with chronic bronchitis have not only decreased ATP concentrations in their airway surface liquid but also ATP levels below the ones needed for signaling (39).…”

Section: Discussionsupporting

confidence: 89%

Dual Oxidase 2 (Duox2) Regulates Pannexin 1-mediated ATP Release in Primary Human Airway Epithelial Cells via Changes in Intracellular pH and Not H2O2 Production

Krick¹,

Wang

St-Pierre³

et al. 2016

Journal of Biological Chemistry

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ATP is a key regulator of the innate pulmonary host defense by activating purinergic P2Y2 receptors, which promote chloride secretion by calcium-activated Cl Ϫ channels, inhibit Na ϩ absorption by epithelial Na ϩ channels, increase ciliary beat frequency and airway surface liquid volume, and induce mucin release, thereby activating mucociliary clearance (1-4).Although the effects of ATP on airway epithelial cells have been studied widely, Panx1 channels have only been recognized recently to be involved in ATP release in these tissues (5, 6). Mechanical stress has been shown to be one of the prime stimuli to increase the ATP concentration on the airway surface to a concentration sufficient to activate P2Y2 receptors (7). This ATP release was neither dependent on the intracellular calcium concentration, excluding an exocytotic release mechanism, nor caused by the cystic fibrosis transmembrane conductance regulator. In previous studies, we were the first to show that Panx1, an ortholog of the invertebrate innexin, is expressed at the apical membrane of airway epithelia, contributing to ATP release (5).Pannexin proteins form pannexons, which are channels that open at resting membrane potential because of mechanical stress and in response to extracellular ATP when co-expressed with P2Y2 receptors (8, 9). In addition to stimulated ATP release, resting ATP levels on the apical surface reflect a steady state that, depending on its range, can help autoregulate the release or metabolism of ATP.Currently little is known about the physiological regulation of pannexin channels in the airway epithelium. Most studies have been performed on oocytes or transfected HEK cells. These studies demonstrated that ATP itself is a potent regulator by increasing the permeability of Panx1 initially when coexpressed with P2Y2 receptors but, consequently, causing inhibition as a feedback loop (10, 11).The cytokine IFN-␥ is produced in inflammatory airway diseases such as severe asthma (12, 13) and chronic bronchitis with and without airflow obstruction (14). We have shown that IFN-␥ can increase H 2 O 2 production via increased expression of Duox2, a member of the NADPH oxidase gene family, in ALI 2 cultures (15, 16). In addition to H 2 O 2 , Duox also releases cytosolic H ϩ (17), which could contribute to intracellular acidification. Consequently, a decrease in intracellular pH could decrease mucociliary function by direct inhibition of the ciliary beat frequency (18). In fact, Duox is up-regulated in chronic bronchitis and patients with smoke exposure (15,19,20). Preliminary data also suggested that intracellular pH is essential in

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Section: Discussionsupporting

confidence: 89%

Dual Oxidase 2 (Duox2) Regulates Pannexin 1-mediated ATP Release in Primary Human Airway Epithelial Cells via Changes in Intracellular pH and Not H2O2 Production

Krick¹,

Wang

St-Pierre³

et al. 2016

Journal of Biological Chemistry

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“…Therefore, we examined the nucleotide content in sputum samples (believed to reflect secretions from the large airways) [38] obtained from CF patients with moderate or severe lung disease and from healthy control subjects. As indicated in Table 1, CF patients exhibited decreased pulmonary function (assessed as forced expiratory volume, FEV1% predicted) and increased (but broadly spread) number of neutrophils in sputum.…”

Section: Resultsmentioning

confidence: 99%

UDP-glucose promotes neutrophil recruitment in the lung

Sesma

Weitzer

Livraghi‐Butrico

et al. 2016

Purinergic Signalling

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In addition to their role in glycosylation reactions, UDP-sugars are released from cells and activate widely distributed cell surface P2Y 14 receptors (P2Y 14 R). However, the physiological/pathophysiological consequences of UDPsugar release are incompletely defined. Here, we report that UDP-glucose levels are abnormally elevated in lung secretions from patients with cystic fibrosis (CF) as well as in a mouse model of CF-like disease, the βENaC transgenic (Tg) mouse. Instillation of UDP-glucose into wild-type mouse tracheas resulted in enhanced neutrophil lung recruitment, and this effect was nearly abolished when UDP-glucose was coinstilled with the P2Y 14 R antagonist PPTN [4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl-2-naphthoic acid]. Importantly, administration of PPTN to βENaC-Tg mice reduced neutrophil lung inflammation. These results suggest that UDP-glucose released into the airways acts as a local mediator of neutrophil inflammation.

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“…121 For example, a recent study found that the total solids content was reduced in induced versus bronchoscopy-derived (i.e., undiluted) samples from the same patients. 122 In contrast, spontaneously expectorated sputum can be used with negligible concern of sample dilution. However, spontaneously expectorated samples are generally produced by patients who have a respiratory disease, such as CF, COPD or asthma.…”

Section: Mucus Samples Used To Assess Mucus Barrier Properties Sourcementioning

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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The Relationship of Mucus Concentration (Hydration) to Mucus Osmotic Pressure and Transport in Chronic Bronchitis

Cited by 135 publications

References 54 publications

Dual Oxidase 2 (Duox2) Regulates Pannexin 1-mediated ATP Release in Primary Human Airway Epithelial Cells via Changes in Intracellular pH and Not H2O2 Production

Dual Oxidase 2 (Duox2) Regulates Pannexin 1-mediated ATP Release in Primary Human Airway Epithelial Cells via Changes in Intracellular pH and Not H2O2 Production

UDP-glucose promotes neutrophil recruitment in the lung

The Mucus Barrier to Inhaled Gene Therapy

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