Saliva Secretion and Epithelial Transport From Classical Models to Modern Developments

Abstract

Saliva secretion, produced by the epithelial cells of the salivary glands, is required for the basic functions of eating and speaking, as well as the maintenance of oral health and comfort. Epithelia in general provide crucial barrier, homeostatic, absorptive and secretory functions in the body. This thesis presents original contributions to the understanding of fluid and solute transport by the salivary glands and other epithelia. Despite many years of investigation, debates over mechanisms and pathways of transport remain. Focus was given here to mathematical and computational investigation of water transport via the osmotic mechanism and its coupling to underlying mechanisms of ion transport. The effect of aquaporin knockout studies, acinus structure and different patterns of calcium signalling on this coupling was investigated. Quasi-steady-state, perturbation and scaling methods were used to analyse dynamic, cellular and multicellular mathematical models of osmotically-driven primary saliva secretion. Comparisons between different epithelia were carried out through the use of a simple, general model of fluid transport applicable to both secretory and absorptive epithelia. These analyses were used to provide new interpretations and understanding of aquaporin knockout experiments in the salivary glands and epithelia in general. The effect of asynchronous calcium signals on cellular saliva secretion was analysed by deriving a new approximate mathematical model. This captured the key features of a more complex computational model developed by other researchers at the University of Auckland. A novel application of rearrangement inequalities was used to analyse global model properties. The dynamic coupling of saliva secretion was found to be positively affected by small lumenal volumes and large water permeabilities. Secretion was shown to be maximised when calcium signal delays between membranes are short. These results are significant because both observations are consistent with the relatively long, thin intercellular canaliculi of salivary acini having important functional roles, such as globalisation of calcium signals and enhancement of osmotic coupling. Transcellular osmosis was found to sufficiently predict the results of aquaporin and combined aquaporin/claudin knockout studies, despite recent opinions to the contrary. We found that significant tight-junctional water fluxes likely do not exist, or at least give no better explanation of non-aquaporin-mediated water transport than remaining cellular permeability. These results are significant because they provide clear quantitative interpretations for knockout studies. This is crucial for predicting and optimising future medical treatments that utilise genetic knockins/ knockouts.