Network thermodynamic analysis and stimulation of isotonic solute-coupled volume flow in leaky epithelia: an example of the use of network theory to provide the qualitative aspects of a complex system and its verification by stimulation.

A network thermodynamic model was developed to provide insights into the nature of isotonic solute-coupled volume flow in "leaky" epithelia, where the transepithelial volume flow is assumed to be primarily through the cellular pathway. The coupled flows of solute and volume at each membrane in this four membrane model are described by the practical phenomenological equations as developed by Kedem & Katchalsky (1958). The model contains one permeable non-electrolyte solute (s) and a fixed amount of an impermeable non-electrolyte (i) inside the cell. The cell is assumed to be capable of volume regulation under the steady-state experimental conditions simulated. A solute-pump, located in the basolateral membrane, uses feedback regulation to adjust Cs in the cell in order to maintain cell volume at or near control levels in all simulations. Model behavior is, in general, very consistent with experimental observations with respect to tonicity and magnitude of volume flow over a wide range of experimental conditions. Examination of the parameter space suggests the following important features when isotonic solute-coupled volume flow moves primarily through the cellular pathway: (1) the apical membrane reflection coefficient must be less than that of the basolateral membrane; (2) the basement membrane reflection coefficient must be small; (3) the apical membrane solute permeability and reflection coefficient are the two most "sensitive" parameters and need to vary in an inverse manner in order to maintain isotonicity when both solute and volume flows increase; and (4) relationships (1) and (3) above imply the need for at least two separate solute pathways in the apical membrane, one that is shared with volume flow and one that is not.