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Sphingomyelinase decreases transepithelial anion secretion in airway epithelial cells in part by inhibiting CFTR-mediated apical conductance.
Cottrill, Kirsten A; Peterson, Raven J; Lewallen, Colby F; Koval, Michael; Bridges, Robert J; McCarty, Nael A.
Afiliación
  • Cottrill KA; Molecular and Systems Pharmacology PhD Program, Emory University, Atlanta, Georgia, USA.
  • Peterson RJ; Biochemistry, Cell, and Developmental Biology PhD Program, Emory University, Atlanta, Georgia, USA.
  • Lewallen CF; Georgia Institute of Technology, G.W. Woodruff School of Mechanical Engineering, Atlanta, Georgia, USA.
  • Koval M; Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, Atlanta, Georgia, USA.
  • Bridges RJ; Department of Cell Biology, Emory University, Atlanta, Georgia, USA.
  • McCarty NA; Department of Physiology and Biophysics, Center for Genetic Diseases, Chicago Medical School, North Chicago, Illinois, USA.
Physiol Rep ; 9(15): e14928, 2021 08.
Article en En | MEDLINE | ID: mdl-34382377
The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel whose dysfunction causes cystic fibrosis (CF). The loss of CFTR function in pulmonary epithelial cells causes surface dehydration, mucus build-up, inflammation, and bacterial infections that lead to lung failure. Little has been done to evaluate the effects of lipid perturbation on CFTR activity, despite CFTR residing in the plasma membrane. This work focuses on the acute effects of sphingomyelinase (SMase), a bacterial virulence factor secreted by CF relevant airway bacteria which degrades sphingomyelin into ceramide and phosphocholine, on the electrical circuitry of pulmonary epithelial monolayers. We report that basolateral SMase decreases CFTR-mediated transepithelial anion secretion in both primary bronchial and tracheal epithelial cells from explant tissue, with current CFTR modulators unable to rescue this effect. Focusing on primary cells, we took a holistic ion homeostasis approach to determine a cause for reduced anion secretion following SMase treatment. Using impedance analysis, we determined that basolateral SMase inhibits apical and basolateral conductance in non-CF primary cells without affecting paracellular permeability. In CF primary airway cells, correction with clinically relevant CFTR modulators did not prevent SMase-mediated inhibition of CFTR currents. Furthermore, SMase was found to inhibit only apical conductance in these cells. Future work should determine the mechanism for SMase-mediated inhibition of CFTR currents, and further explore the clinical relevance of SMase and sphingolipid imbalances.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esfingomielina Fosfodiesterasa / Staphylococcus aureus / Tráquea / Bronquios / Regulador de Conductancia de Transmembrana de Fibrosis Quística / Células Epiteliales / Aniones Límite: Humans Idioma: En Revista: Physiol Rep Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esfingomielina Fosfodiesterasa / Staphylococcus aureus / Tráquea / Bronquios / Regulador de Conductancia de Transmembrana de Fibrosis Quística / Células Epiteliales / Aniones Límite: Humans Idioma: En Revista: Physiol Rep Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos