Abstract:
Mucociliary transport provides the airways' vanguard of defence against inspired noxious materials. Without adequate hydration of the thin layer of liquid that lines the airways, mucociliary transport would cease, leading to build up of mucus and the development of infection. Within this thesis a multi-scale computational model was used to investigate the fluid transport within the airways which is necessary for maintenance of the mucociliary transport system. A mathematical description of the fluid secretion elicited by a rise in [Ca2+]i from a single airway epithelial cell was developed. The model indicates that apical membrane Ca2+ activated Cl- channels are not required for Ca2+ induced fluid secretion. It was shown that when [Ca2+]i followed an oscillatory profile the resulting fluid secretion displayed different properties to when the model stimulated a tonic rise in [Ca2+]i due to saturation of the Ca2+ gated ion channels. Furthermore, consistent with known physiology, cell volume returned to equilibrium more rapidly after a hypotonic challenge when Ca2+ gated ion channels were activated by a rise in [Ca2+]i. A description of intercellular Ca2+ signalling was developed and used to investigate the relative roles of IP3 and ATP diffusion in mediating [Ca2+]i waves in airway epithelial tissue. It was shown that for greater amounts of released ATP, there is a diminishing return in the radius of [Ca2+]i wave propagation. In addition to this, the radial profile of maximal [Ca2+]i response from the stimulated cell does not match the flat profile seen in experimental studies. This suggests that for [Ca2+]i waves to propagate large distances an additional mechanism such as regenerative release of ATP from cells down stream of the stimulated cell may be important. The epithelial cell model was incorporated into a geometric representation of the human conducting airways. This “cell to organ” coupling was used to investigate the transport of water and heat within the airways. The current work indicates that energy neutrality on its own is an unsatisfactory metric of inspired air's temperature and humidity for invasive mechanical ventilation and can lead to airway dehydration. It was shown that with inspiration of air significantly above body core temperature, a redistribution of airway surface liquid can theoretically occur. This condition represents an extreme which is unlikely to occur clinically, and suggests that mild heating of the air within the ventilator circuit would not cause mucociliary transport dysfunction. The model presented here provides a firm platform for further study of pathological conditions, such as cystic fibrosis, which lead to mucociliary failure.