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      Cyclic compression increases F508 Del CFTR expression in ciliated human airway epithelium

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          Abstract

          The mechanisms by which transepithelial pressure changes observed during exercise and airway clearance can benefit lung health are challenging to study. Here, we have studied 117 mature, fully ciliated airway epithelial cell filters grown at air-liquid interface grown from 10 cystic fibrosis (CF) and 19 control subjects. These were exposed to cyclic increases in apical air pressure of 15 cmH 2O for varying times. We measured the effect on proteins relevant to lung health, with a focus on the CF transmembrane regulator (CFTR). Immunoflourescence and immunoblot data were concordant in demonstrating that air pressure increased F508Del CFTR expression and maturation. This effect was in part dependent on the presence of cilia, on Ca 2+ influx, and on formation of nitrogen oxides. These data provide a mechanosensory mechanism by which changes in luminal air pressure, like those observed during exercise and airway clearance, can affect epithelial protein expression and benefit patients with diseases of the airways.

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          Most cited references 63

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          Motile cilia of human airway epithelia are chemosensory.

          Cilia are microscopic projections that extend from eukaryotic cells. There are two general types of cilia; primary cilia serve as sensory organelles, whereas motile cilia exert mechanical force. The motile cilia emerging from human airway epithelial cells propel harmful inhaled material out of the lung. We found that these cells express sensory bitter taste receptors, which localized on motile cilia. Bitter compounds increased the intracellular calcium ion concentration and stimulated ciliary beat frequency. Thus, airway epithelia contain a cell-autonomous system in which motile cilia both sense noxious substances entering airways and initiate a defensive mechanical mechanism to eliminate the offending compound. Hence, like primary cilia, classical motile cilia also contain sensors to detect the external environment.
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            A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia.

            Mucus clearance is the primary defense mechanism that protects airways from inhaled infectious and toxic agents. In the current gel-on-liquid mucus clearance model, a mucus gel is propelled on top of a "watery" periciliary layer surrounding the cilia. However, this model fails to explain the formation of a distinct mucus layer in health or why mucus clearance fails in disease. We propose a gel-on-brush model in which the periciliary layer is occupied by membrane-spanning mucins and mucopolysaccharides densely tethered to the airway surface. This brush prevents mucus penetration into the periciliary space and causes mucus to form a distinct layer. The relative osmotic moduli of the mucus and periciliary brush layers explain both the stability of mucus clearance in health and its failure in airway disease.
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              A metabolic enzyme for S-nitrosothiol conserved from bacteria to humans.

              Considerable evidence indicates that NO biology involves a family of NO-related molecules and that S-nitrosothiols (SNOs) are central to signal transduction and host defence. It is unknown, however, how cells switch off the signals or protect themselves from the SNOs produced for defence purposes. Here we have purified a single activity from Escherichia coli, Saccharomyces cerevisiae and mouse macrophages that metabolizes S-nitrosoglutathione (GSNO), and show that it is the glutathione-dependent formaldehyde dehydrogenase. Although the enzyme is highly specific for GSNO, it controls intracellular levels of both GSNO and S-nitrosylated proteins. Such 'GSNO reductase' activity is widely distributed in mammals. Deleting the reductase gene in yeast and mice abolishes the GSNO-consuming activity, and increases the cellular quantity of both GSNO and protein SNO. Furthermore, mutant yeast cells show increased susceptibility to a nitrosative challenge, whereas their resistance to oxidative stress is unimpaired. We conclude that GSNO reductase is evolutionarily conserved from bacteria to humans, is critical for SNO homeostasis, and protects against nitrosative stress.
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                Author and article information

                Journal
                American Journal of Physiology-Lung Cellular and Molecular Physiology
                American Journal of Physiology-Lung Cellular and Molecular Physiology
                American Physiological Society
                1040-0605
                1522-1504
                August 2019
                August 2019
                : 317
                : 2
                : L247-L258
                Affiliations
                [1 ]Pediatric Pulmonology Division, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio
                [2 ]W. M. Keck Center for Cellular Imaging, Department of Biology, University of Virginia, Charlottesville, Virginia
                [3 ]Lake Effect Pharma, LLC, Gates Mills, Ohio
                [4 ]Department of Pediatrics, Division of Pulmonary Medicine, Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, Virginia
                [5 ]Thoracic Surgery Service, Memorial Sloan Kettering Cancer Center, New York, New York
                [6 ]Pulmonology and Critical Care Medicine University Hospitals, Cleveland, Ohio
                [7 ]Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina
                [8 ]Pediatric Pulmonology Division, Rainbow Babies and Children’s Hospital, Cleveland, Ohio
                Article
                10.1152/ajplung.00020.2019
                © 2019

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