Computational Modelling of Fluid and Ion Transport in the Epithelial Cell

Abstract

Secretory epithelia line organs in the human body, and exquisitely control fluid and solute transport between interior and external cavities. Dysregulation results in abnormal fluid secretion rates, leading to disease. We developed a mathematical model of a generic epithelial cell to simulate these transport processes. This system can be adapted to model transport across different epithelia - here, it was used to obtain insight into normal and pathological conditions in salivary and alveolar epithelia. Regarding saliva secretion, clinical trials have shown that irradiated parotid glands with low salivary output saw a partial restoration following transfection of aquaporin, contradicting the traditional view which predicted that fluid be absorbed out of saliva instead. To help explain this, several units of the single cell were combined into a model of the parotid duct. Model results were most aligned to experimental data when a subgroup of water permeable cells were introduced to the proximal duct, and received the majority of the transfected aquaporin. Coupled with alterations in channel expression, these changes led to increased secretion, and predicted higher bicarbonate content in the final saliva. We also fitted the generic model with characteristics of an alveolar epithelial cell, and compared against experimental observations. At baseline, it was found that the cell was absorptive, where transcellular sodium flux dominated; chloride flux was 200 times smaller. It was found that blocking the cystic fibrosis transmembrane regulator had limited impact at baseline, but was the key to the transport of fluid in both normal and edematous states. Nucleotide signalling was also incorporated into the alveolar cell model, where mechanical forces increased the rate of nucleotide secretion. We found that periodic stretch increased apical liquid volume, which led to flooding at prolonged straining beyond the range of tidal breathing. Desensitisation of purinoceptors helped prevent flooding if there were high adenosine triphosphate levels. Functional apical chloride transport was necessary for fluid secretion into the lumen. Our generic model shows that regulation of fluid transport is complex. By reproducing trends that were observed experimentally, the model could be used to highlight pathways to be exploited in the treatment of diseases induced by defective transport.