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  1. Article: Epithelial vectorial ion transport in cystic fibrosis: Dysfunction, measurement, and pharmacotherapy to target the primary deficit.

    Clunes, Lucy A / McMillan-Castanares, Naia / Mehta, Neil / Mesadieu, Afia / Rodriguez, Jorge / Maj, Mary / Clunes, Mark T

    SAGE open medicine

    2020  Volume 8, Page(s) 2050312120933807

    Abstract: Cystic fibrosis patients display multi-organ system dysfunction (e.g. pancreas, gastrointestinal tract, and lung) with pathogenesis linked to a failure of ... ...

    Abstract Cystic fibrosis patients display multi-organ system dysfunction (e.g. pancreas, gastrointestinal tract, and lung) with pathogenesis linked to a failure of Cl
    Language English
    Publishing date 2020-06-25
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2735399-0
    ISSN 2050-3121
    ISSN 2050-3121
    DOI 10.1177/2050312120933807
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Epithelial vectorial ion transport in cystic fibrosis

    Lucy A Clunes / Naia McMillan-Castanares / Neil Mehta / Afia Mesadieu / Jorge Rodriguez / Mary Maj / Mark T Clunes

    SAGE Open Medicine, Vol

    Dysfunction, measurement, and pharmacotherapy to target the primary deficit

    2020  Volume 8

    Abstract: Cystic fibrosis patients display multi-organ system dysfunction (e.g. pancreas, gastrointestinal tract, and lung) with pathogenesis linked to a failure of Cl − secretion from the epithelial surfaces of these organs. If unmanaged, organ dysfunction starts ...

    Abstract Cystic fibrosis patients display multi-organ system dysfunction (e.g. pancreas, gastrointestinal tract, and lung) with pathogenesis linked to a failure of Cl − secretion from the epithelial surfaces of these organs. If unmanaged, organ dysfunction starts early and patients experience chronic respiratory infection with reduced lung function and a failure to thrive due to gastrointestinal malabsorption. Early mortality is typically caused by respiratory failure. In the past 40 years of newborn screening and improved disease management have driven the median survival up from the mid-teens to 43–53, with most of that improvement coming from earlier and more aggressive management of the symptoms. In the last decade, promising pharmacotherapies have been developed for the correction of the underlying epithelial dysfunction, namely, Cl − secretion. A new generation of systemic drugs target the mutated Cl − channels in cystic fibrosis patients and allow trafficking of the immature mutated protein to the cell membrane (correctors), restore function to the channel once in situ (potentiators), or increase protein levels in the cells (amplifiers). Restoration of channel function prior to symptom development has the potential to significantly change the trajectory of disease progression and their evidence suggests that a modest restoration of Cl − secretion may delay disease progression by decades. In this article, we review epithelial vectorial ion and fluid transport, its quantification and measurement as a marker for cystic fibrosis ion transport dysfunction, and highlight some of the recent therapies targeted at the dysfunctional ion transport of cystic fibrosis.
    Keywords Medicine (General) ; R5-920
    Subject code 610
    Language English
    Publishing date 2020-06-01T00:00:00Z
    Publisher SAGE Publishing
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Introduction to section I: overview of approaches to study cystic fibrosis pathophysiology.

    Clunes, Mark T / Boucher, Richard C

    Methods in molecular biology (Clifton, N.J.)

    2011  Volume 742, Page(s) 3–14

    Abstract: Mutation of the CFTR chloride channel was identified as the genetic basis of cystic fibrosis over 20 years ago; however, correlation of the pathophysiological changes occurring in CF lung disease with the mutation of a chloride channel is ongoing. The ... ...

    Abstract Mutation of the CFTR chloride channel was identified as the genetic basis of cystic fibrosis over 20 years ago; however, correlation of the pathophysiological changes occurring in CF lung disease with the mutation of a chloride channel is ongoing. The failure of innate lung defense in CF, and the subsequent cyclical microbial colonization of airways, explains the gross anatomical changes that occur in CF pathophysiology. However, ongoing research is focused on how the lack of the CFTR channel explains the failure of innate lung defense. Hydration status of the mucus blanket is key to understanding this link, and this series of chapters details the recent progress that has been made in understanding the interplay between ion transport activity and innate lung defense, and the initiation of CF lung pathophysiology.
    MeSH term(s) Airway Remodeling ; Animals ; Bacterial Infections/microbiology ; Bacterial Infections/physiopathology ; Biofilms ; Biological Transport ; Cystic Fibrosis/genetics ; Cystic Fibrosis/metabolism ; Cystic Fibrosis/microbiology ; Cystic Fibrosis/physiopathology ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Dehydration/metabolism ; Dehydration/physiopathology ; Humans ; Inflammation/metabolism ; Inflammation/microbiology ; Inflammation/physiopathology ; Lung/metabolism ; Lung/microbiology ; Lung/physiopathology ; Mice ; Mucociliary Clearance ; Mucus/metabolism ; Mucus/microbiology ; Mutation ; Neutrophil Infiltration ; Osmotic Pressure ; Research Design ; Water/metabolism
    Chemical Substances Water (059QF0KO0R) ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
    Language English
    Publishing date 2011
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-61779-120-8_1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Cystic Fibrosis: The Mechanisms of Pathogenesis of an Inherited Lung Disorder.

    Clunes, Mark T / Boucher, Richard C

    Drug discovery today. Disease mechanisms

    2008  Volume 4, Issue 2, Page(s) 63–72

    Abstract: Cystic fibrosis patients exhibit lung disease consistent with a failure of innate airway defense mechanisms. The link between abnormal ion transport and disease initiation and progression is not fully understood, but airway mucus dehydration seems ... ...

    Abstract Cystic fibrosis patients exhibit lung disease consistent with a failure of innate airway defense mechanisms. The link between abnormal ion transport and disease initiation and progression is not fully understood, but airway mucus dehydration seems paramount in the initiation of CF lung disease. New therapies are currently in development that target the ion transport defects in CF with the intention of rehydrating airway surfaces.
    Language English
    Publishing date 2008-06-18
    Publishing country England
    Document type Journal Article
    ISSN 1740-6765
    ISSN 1740-6765
    DOI 10.1016/j.ddmec.2007.09.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Front-runners for pharmacotherapeutic correction of the airway ion transport defect in cystic fibrosis.

    Clunes, Mark T / Boucher, Richard C

    Current opinion in pharmacology

    2008  Volume 8, Issue 3, Page(s) 292–299

    Abstract: Although cystic fibrosis (CF) patients display multiorgan dysfunction (e.g. pancreas, gut, and lung) it is lung disease that is the leading cause of premature death in these patients. CF lung disease is characterized by persistent pulmonary infection and ...

    Abstract Although cystic fibrosis (CF) patients display multiorgan dysfunction (e.g. pancreas, gut, and lung) it is lung disease that is the leading cause of premature death in these patients. CF lung disease is characterized by persistent pulmonary infection and mucus plugging of the airways initiated by the failure of solute transport across the airway epithelium. Many drug therapies aim to alleviate the secondary characteristics of CF lung disease; however, new therapies in development are targeted at correcting the ion transport deficiency of CF. The goal is to hydrate airway surfaces by stimulating secretion (through activation of the CF transmembrane conductance regulator and calcium-activated chloride channels), and/or inhibiting absorption (through the epithelial sodium channel) thereby stimulating healthy mucociliary clearance. If mucociliary clearance can be stimulated sufficiently from an early age, then there is the possibility that secondary lung infection may be eradicated from the syndrome of CF disease.
    MeSH term(s) Cystic Fibrosis/drug therapy ; Cystic Fibrosis/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Deoxycytosine Nucleotides/therapeutic use ; Humans ; Ion Transport/drug effects ; Lung/metabolism ; Mannitol/administration & dosage ; Peptides, Cyclic/therapeutic use ; Saline Solution, Hypertonic/therapeutic use ; Sodium Channel Blockers/therapeutic use ; Uridine/analogs & derivatives ; Uridine/therapeutic use
    Chemical Substances Deoxycytosine Nucleotides ; Moli1901 ; Peptides, Cyclic ; Saline Solution, Hypertonic ; Sodium Channel Blockers ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; Mannitol (3OWL53L36A) ; denufosol tetrasodium (82M942WZ4A) ; Uridine (WHI7HQ7H85)
    Language English
    Publishing date 2008-05-28
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2037057-X
    ISSN 1471-4973 ; 1471-4892
    ISSN (online) 1471-4973
    ISSN 1471-4892
    DOI 10.1016/j.coph.2008.04.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5608: Show issues Location:
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  6. Article: Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies.

    Thompson, Miles D / Capra, Valerie / Clunes, Mark T / Rovati, G E / Stankova, Jana / Maj, Mary C / Duffy, David L

    Frontiers in pharmacology

    2016  Volume 7, Page(s) 299

    Abstract: Genetic variants associated with asthma pathogenesis and altered response to drug therapy are discussed. Many studies implicate polymorphisms in genes encoding the enzymes responsible for leukotriene synthesis and intracellular signaling through ... ...

    Abstract Genetic variants associated with asthma pathogenesis and altered response to drug therapy are discussed. Many studies implicate polymorphisms in genes encoding the enzymes responsible for leukotriene synthesis and intracellular signaling through activation of seven transmembrane domain receptors, such as the cysteinyl leukotriene 1 (CYSLTR1) and 2 (CYSLTR2) receptors. The leukotrienes are polyunsaturated lipoxygenated eicosatetraenoic acids that exhibit a wide range of pharmacological and physiological actions. Of the three enzymes involved in the formation of the leukotrienes, arachidonate 5 lipoxygenase 5 (ALOX5), leukotriene C4 synthase (LTC4S), and leukotriene hydrolase (LTA4H) are all polymorphic. These polymorphisms often result in variable production of the CysLTs (LTC4, LTD4, and LTE4) and LTB4. Variable number tandem repeat sequences located in the Sp1-binding motif within the promotor region of the
    Language English
    Publishing date 2016-12-01
    Publishing country Switzerland
    Document type Review ; Journal Article
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2016.00299
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  7. Article ; Online: A2B adenosine receptors regulate the mucus clearance component of the lung's innate defense system.

    Rollins, Brett M / Burn, Mellisa / Coakley, Ray D / Chambers, Lucy A / Hirsh, Andrew J / Clunes, Mark T / Lethem, Michael I / Donaldson, Scott H / Tarran, Robert

    American journal of respiratory cell and molecular biology

    2008  Volume 39, Issue 2, Page(s) 190–197

    Abstract: Adenosine (ADO) signaling is altered in both asthma and chronic obstructive pulmonary disease, and the A(2B) adenosine receptor (A(2B)-R) may drive pulmonary inflammation. Accordingly, it has been proposed that specific inhibition of the A(2B)-R could ... ...

    Abstract Adenosine (ADO) signaling is altered in both asthma and chronic obstructive pulmonary disease, and the A(2B) adenosine receptor (A(2B)-R) may drive pulmonary inflammation. Accordingly, it has been proposed that specific inhibition of the A(2B)-R could treat inflammatory lung diseases. However, stimulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by ADO may be crucial in permitting the superficial epithelium to maintain airway surface liquid (ASL) volume, which is required to ensure hydrated and clearable mucus. Our goal was to determine which ADO receptor (ADO-R) underlies ASL volume regulation in bronchial epithelia. We used PCR techniques to determine ADO-R expression in bronchial epithelia and used nasal potential difference measurements, Ussing chambers studies, and XZ-confocal microscopy to look at Cl- secretion and ASL volume regulation. The A(2B)-R was the most highly expressed ADO-R in donor specimens of human bronchial epithelia, and inhibition of ADO-R in vivo prevented activation of CFTR. A(2B)-R was the only ADO-R detected in cultured human bronchial epithelial cells and inhibition of this receptor with specific A(2B)-R antagonists resulted in ASL height collapse and a failure to effect ASL height homeostasis. Removal of ADO with ADO deaminase and replacement with 5'N-ethylcarboxamide adenosine resulted in dose-dependent changes in ASL height, and suggested that the cell surface (ADO) may be in excess of 1 microM, which is sufficient to activate A(2B)-R. A(2B)-R are required for ASL volume homeostasis in human airways, and therapies directed at inhibiting A(2B)-R may lead to a cystic fibrosis-like phenotype with depleted ASL volume and mucus stasis.
    MeSH term(s) Adenosine/pharmacology ; Adenosine/physiology ; Adenosine A2 Receptor Antagonists ; Adenosine Deaminase/pharmacology ; Adenosine-5'-(N-ethylcarboxamide)/pharmacology ; Bronchi/immunology ; Bronchi/physiology ; Calcium/metabolism ; Cells, Cultured ; Chlorides/metabolism ; Cyclic AMP/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Humans ; Immunity, Innate ; Mucus/physiology ; Receptor, Adenosine A2B/biosynthesis ; Receptor, Adenosine A2B/physiology ; Respiratory Mucosa/immunology ; Respiratory Mucosa/physiology
    Chemical Substances Adenosine A2 Receptor Antagonists ; Chlorides ; Receptor, Adenosine A2B ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; Adenosine-5'-(N-ethylcarboxamide) (35920-39-9) ; Cyclic AMP (E0399OZS9N) ; Adenosine Deaminase (EC 3.5.4.4) ; Adenosine (K72T3FS567) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2008-03-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1025960-0
    ISSN 1535-4989 ; 1044-1549
    ISSN (online) 1535-4989
    ISSN 1044-1549
    DOI 10.1165/rcmb.2007-0450OC
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2851: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  8. Article: Nucleotide-evoked ion transport and [Ca(2+)](i) changes in normal and hyperhidrotic human sweat gland cells.

    Bovell, D L / Clunes, M T / Elder, H Y / Wong, C H / Ko, W H

    European journal of pharmacology

    2000  Volume 403, Issue 1-2, Page(s) 45–48

    Abstract: ... epithelia on permeable supports. Basolateral application to hyperhidrotic cells exhibited a markedly greater ...

    Abstract Apical and basolateral application of ATP and UTP evoked [Ca(2+)](i) and short circuit current (Isc) increases in normal and hyperhidrotic human eccrine sweat gland cells grown into functionally polarised epithelia on permeable supports. Basolateral application to hyperhidrotic cells exhibited a markedly greater increase in Isc than in normal cells. Hyperhidrotic cells also demonstrated differences from the normal in [Ca(2+)](i) and Isc responses to ATP when pre-treated with thapsigargin. The data demonstrate the presence of apical and basolateral receptors that allow nucleotides to increase [Ca(2+)](i) and Isc. The results suggest that changes from the normal in transepithelial ion transport contribute to the characteristic excessive fluid production of hyperhidrotic sweat glands.
    MeSH term(s) Adenosine Triphosphate/pharmacology ; Calcium/metabolism ; Cell Polarity ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Epithelial Cells/physiology ; Humans ; Hyperhidrosis/metabolism ; Hyperhidrosis/physiopathology ; Ion Transport/drug effects ; Membrane Potentials/drug effects ; Sweat Glands/cytology ; Sweat Glands/drug effects ; Sweat Glands/metabolism ; Thapsigargin/pharmacology ; Uridine Triphosphate/pharmacology
    Chemical Substances Thapsigargin (67526-95-8) ; Adenosine Triphosphate (8L70Q75FXE) ; Calcium (SY7Q814VUP) ; Uridine Triphosphate (UT0S826Z60)
    Language English
    Publishing date 2000-09-01
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80121-5
    ISSN 1879-0712 ; 0014-2999
    ISSN (online) 1879-0712
    ISSN 0014-2999
    DOI 10.1016/s0014-2999(00)00570-7
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 522: Show issues Location:
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