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Previous studies have shown that localized delivery of the aquaporin-1 (AQP1) gene to the parotid duct can restore saliva flow in minipigs following irradiation-induced salivary hypofunction. The resulting flow rate and electrochemistry of secreted saliva contradicts current understanding of ductal fluid transport. We hypothesized that changes in expression of ion transport proteins have occurred following AQP1 transfection. We use a mathematical model of ion and fluid transport across the parotid duct epithelial cells to predict the expression profile of ion transporters that are consistent with the experimental measurements of saliva composition and secretion rates. Using a baseline set of parameters, the model reproduces the data for the irradiated, non-AQP1-transfected case. We propose three scenarios which may have occurred after transfection, which differ in the location of the AQP1 gene. The first scenario places AQP1 within nonsecretory cells, and requires that epithelial sodium channel (ENaC) expression is greatly reduced (1.3% of baseline), and ductal bicarbonate concentration is increased from 40.6 to 137.0 mM, to drive water secretion into the duct. The second scenario introduces the AQP1 gene into all ductal cells. The final scenario has AQP1 primarily in the proximal duct cells which secrete water under baseline conditions. We find the change in the remaining cells includes a 95.8% reduction in ENaC expression, enabling us to reproduce all experimental ionic concentrations within 9 mM. These findings provide a mechanistic basis for the observations and will guide the further development of gene transfer therapy for salivary hypofunction.

Computational modeling of epithelial fluid and ion transport in the parotid duct after transfection of human aquaporin-1