Understanding saliva secretion through mathematical modelling

Abstract

Hyposalivation is a burden for many individuals. Medications and therapies to treat cancer and other diseases increase the risk of poor salivary flow. This thesis aims to contribute to the vast research devoted to saliva production. It focuses on the secretory machinery of the salivary gland acinar cell. Although the molecular mechanisms involved are well known, their transport properties remain controversial. In these epithelia the driving force for fluid secretion is generated by the transcellular passage of Cl- ions. A basolateral Na+-K+-2Cl- cotransporter, energised by a Na+/K+ ATPase pump, promotes the accumulation of Cl- above its equilibrium potential. Studies have demonstrated that disruption of the cotransporter’s activity partially impairs salivation, indicating the presence of a parallel mechanism that supports Cl- uptake. Recent experiments revealed that under sustained salivation, mice glands devoid of Na+-dependent Cl-/HCO- 3 anion exchanger 4 (Ae4) expression exhibit a decreased secretion rate. In contrast, mice lacking the Cl-/HCO- 3 anion exchanger 2 (Ae2) display a normal salivary flow. The result is contradictory to previous hypotheses that suggest the Ae2 is an important Cl- uptake pathway involved in fluid transport. We developed a realistic computational representation of the acinar cell that extends previous models to account for a paired pH regulating and HCO- 3 -dependent Cl- uptake system. We investigate the extent of its involvement in fluid secretion through Ae2 and Ae4 knockout simulations. Under salivation conditions the Ae4 knockout model exhibits a 26% reduction in salivary flow rate. Removal of the Ae2, on the other hand, did not affect secretion. Based on a careful analysis of the model results and predictions, we claim that this may be a direct consequence of the Ae4 cotransport properties. To verify our results we also performed Cl- uptake simulations. These consisted in removing nearly all intracellular Cl- and allowing the cell to retake the ion exclusively through the Ae2 and Ae4 mechanisms. The Ae4 null model displayed a lower Cl- uptake rate compared to the Ae2 knockout, whose uptake rate was nearly identical to the control cell. The results of this study indicate that expression of the Ae4 exchanger is crucial for fluid transport during secretion of salivary gland acinar cells.