A physiologically-motivated model of cystic fibrosis liquid and solute transport dynamics across primary human nasal epithelia
Cystic fibrosis (CF) disease is caused by mutations affecting the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel expressed in the mucosal side of epithelial tissue. In the airway, dysfunctional CFTR results in a transepithelial osmotic imbalance leading to hyperabsorption of airway surface liquid mucostasis, chronic inflammation, and eventual respiratory failure. Human nasal epithelial cell cultures from healthy and CF donors were used to perform studies of liquid and solute transport dynamics at an air/liquid interface in order to emulate the in vivo airway. Then, these results were used to inform a quantitative systems pharmacology model of airway epithelium describing electrically and chemically driven transcellular ionic transport, contributions of both convective and diffusive paracellular solute transport, and osmotically driven transepithelial water dynamics. Model predictions showed CF cultures, relative to non-CF ones, have increased apical and basolateral water permeabilities, and increase paracellular permeability and transepithelial chemical driving force for a radiolabeled tracer used to track small molecule absorption. These results provide a computational platform to better understand and probe the mechanisms behind the liquid hyperabsorption and small molecule retention profiles observed in the CF airway.
KeywordsCystic fibrosis CFTR Quantitative systems pharmacology Human nasal epithelial Airway surface liquid layer Electrophysiology
The authors thank Stefanie Coburn and Sheila Frizzell for their technical assistance with cell cultures, and Mary Joens, Matthew Markovetz, Ph.D., and William Confer for contributions to model development and implementation. As well as funding from the National Institutes of Health Grants # R01 HL108929-01 and U01 HL131046-01.
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