Model of mucociliary clearance in cystic fibrosis lungs.
Mucus clearance is a primary innate defense mechanism in the human airways. Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CF is characterized by dehydration of airway surface liquid and impaired mucociliary clearance. As a result, microorganisms are not efficiently removed from the airways, and patients experience chronic pulmonary infections and inflammation. We propose a new physiologically based mathematical model of muco-ciliary transport consisting of the two major components of the mucociliary clearance system: (i) periciliary liquid layer (PCL) and (ii) mucus layer. We study mucus clearance under normal conditions and in CF patients. Restoring impaired clearance of airway secretions in one of the major goals of therapy in patients with CF. We consider the action of the aerosolized and inhaled medication dornase alfa, which reduces the viscosity of cystic fibrosis mucus, by selectively cleaving the long DNA strands it contains. The results of the model simulations stress the potential relevance of the location of the drug deposition in the central or peripheral airways. Mucus clearance was increased in case the drug was primarily deposited peripherally, i.e. in the small airways.
University of Lyon 1, UMR 5558, CRNS Lyon, 8 rue Guillaume Paradin, BP8071, 69376 cedex 08, Lyon, France; UMR 663, Inserm-University Paris Descartes-CEA, Necker Hospital, Paris, France. Electronic address: polina.kurbatova@univ-lyon1.fr.
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Kurbatova
Institute of Mechanical Engineering Problems, 199178 Saint Petersburg, Russia.
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Bessonov
University of Lyon 1, CNRS UMR 5208, Institut Camille Jordan 43 blvd du 11 novembre 1918, F-69622 Villeurbanne-Cedex, France.
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Volpert
Erasmus University Medical Centre-Sophia Children׳s Hospital, PO Box 2060, 3000 CB Rotterdam, Netherlands.
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Tiddens
University of Lyon 1, UMR 5558, CRNS Lyon, 8 rue Guillaume Paradin, BP8071, 69376 cedex 08, Lyon, France; CHU Lyon, Service de Pharmacologie Clinique, 8 rue Guillaume Paradin, BP8071, 69376 cedex 08, Lyon, France; Hôpital Louis Pradel, Centre d׳Investigation Clinique, INSERM CIC201/UMR5558, Bron, France.
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Cornu
University of Lyon 1, UMR 5558, CRNS Lyon, 8 rue Guillaume Paradin, BP8071, 69376 cedex 08, Lyon, France; CHU Lyon, Service de Pharmacologie Clinique, 8 rue Guillaume Paradin, BP8071, 69376 cedex 08, Lyon, France.
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Nony
Erasmus University Medical Centre-Sophia Children׳s Hospital, PO Box 2060, 3000 CB Rotterdam, Netherlands.
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Caudri
D000280:Administration, Inhalation; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004247:DNA / Q000737:chemistry; D003850:Deoxyribonuclease I / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000503:physiopathology*; D008954:Models, Biological; D009079:Mucociliary Clearance; D009093:Mucus / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012137:Respiratory System / Q000473:pathology; D014783:Viscosity
C505032:CFTR protein, human; D011994:Recombinant Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004247:DNA; D003850:Deoxyribonuclease I; C568813:dornase alfa
Aerosol drug therapy; Dornase alfa; Mathematical model; Mucoviscidosis; Mucus transport