Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis
| Autor: | Lhousseine Touqui, Sabrina Noël, Bérengère Villeret, Gilles Crambert, Isabelle Sermet-Gaudelus, Nesrine Baatallah, Aleksander Edelman, Elise Dreano, Emmanuelle Bille, Anita Golec, Aurélie Hatton, Juliette Simonin, Valérie Urbach, Xavier Nassif, Luis J. V. Galietta, Charles-Henry Cottart, Gabrielle Planelles, Alexandre Hinzpeter, Iwona Pranke, Jean-Michel Sallenave, Jean-Patrick Vrel, Aurélie Edwards |
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| Přispěvatelé: | Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Sorbonne Paris Cité (USPC), Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Boston University [Boston] (BU), Institut Pasteur [Paris] (IP), Université Paris Descartes - Paris 5 (UPD5), The last part of the project is funded through Vertex Innovation Award (VIA) which is an unconditional research grant provided by Vertex Pharmaceuticals (Europe) Limited. Equipment funding. supported by University Paris Descartes. Gifts of the CFTR PPQ-102 and pendrin A01 inhibitors by Dr. Alan Verkman., Gestionnaire, Hal Sorbonne Université, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Simonin, J., Bille, E., Crambert, G., Noel, S., Dreano, E., Edwards, A., Hatton, A., Pranke, I., Villeret, B., Cottart, C. -H., Vrel, J. -P., Urbach, V., Baatallah, N., Hinzpeter, A., Golec, A., Touqui, L., Nassif, X., Galietta, L. J. V., Planelles, G., Sallenave, J. -M., Edelman, A., Sermet-Gaudelus, I., Institut Pasteur [Paris], École Pratique des Hautes Études (EPHE) |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator lcsh:Medicine [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract Cystic fibrosis Ouabain H(+)-K(+)-Exchanging ATPase 0302 clinical medicine Respiratory system Child lcsh:Science Cells Cultured ComputingMilieux_MISCELLANEOUS Multidisciplinary biology Chemistry Hydrogen-Ion Concentration Staphylococcal Infections respiratory system Cystic fibrosis transmembrane conductance regulator 3. Good health [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biophysics [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology Sulfate Transporters Child Preschool [SDV.IMM]Life Sciences [q-bio]/Immunology medicine.drug Staphylococcus aureus Cell biology [SDV.IMM] Life Sciences [q-bio]/Immunology Antimicrobial peptides Bronchi Respiratory Mucosa [SDV.BC]Life Sciences [q-bio]/Cellular Biology Microbiology Article Cell Line 03 medical and health sciences Cathelicidins [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] otorhinolaryngologic diseases medicine Humans Secretion [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] Author Correction lcsh:R Infant Newborn Infant Epithelial Cells Pendrin medicine.disease Bicarbonates 030104 developmental biology Cell culture [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology biology.protein [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract lcsh:Q 030217 neurology & neurosurgery Antimicrobial Cationic Peptides |
| Zdroj: | Scientific Reports Scientific Reports, 2019, 9, pp.6516. ⟨10.1038/s41598-019-42751-4⟩ Scientific Reports, Nature Publishing Group, 2019, 9 (1), ⟨10.1038/s41598-019-42751-4⟩ Scientific Reports, Vol 9, Iss 1, Pp 1-11 (2019) Scientific Reports, Nature Publishing Group, 2019, 9, pp.6516. ⟨10.1038/s41598-019-42751-4⟩ |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-019-42751-4 |
| Popis: | Cystic fibrosis (CF) is caused by defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. Morbidity is mainly due to early airway infection. We hypothesized that S. aureus clearance during the first hours of infection was impaired in CF human Airway Surface Liquid (ASL) because of a lowered pH. The ASL pH of human bronchial epithelial cell lines and primary respiratory cells from healthy controls (WT) and patients with CF was measured with a pH microelectrode. The antimicrobial capacity of airway cells was studied after S. aureus apical infection by counting surviving bacteria. ASL was significantly more acidic in CF than in WT respiratory cells. This was consistent with a defect in bicarbonate secretion involving CFTR and SLC26A4 (pendrin) and a persistent proton secretion by ATP12A. ASL demonstrated a defect in S. aureus clearance which was improved by pH normalization. Pendrin inhibition in WT airways recapitulated the CF airway defect and increased S. aureus proliferation. ATP12A inhibition by ouabain decreased bacterial proliferation. Antimicrobial peptides LL-37 and hBD1 demonstrated a pH-dependent activity. Normalizing ASL pH might improve innate airway defense in newborns with CF during onset of S. aureus infection. Pendrin activation and ATP12A inhibition could represent novel therapeutic strategies to normalize pH in CF airways. |
| Databáze: | OpenAIRE |
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