Abstract
Purpose::
Acinar cells in the lacrimal gland are important in tear production. Water movement by osmosis follows solute transport from the serosal side to lumen. The onset of tear secretion is accompanied by cell shrinkage, which reflects a net reduction in cell solute content. Acinar cells also display a regulatory volume increase (RVI) response to exposure to elevated extracellular osmolarity. In both cases, the Na+-K+-2Cl- co-transporter (NKCC1) activity increases which loads Cl- into the cells.
Methods::
To explore the relationship between volume regulation and tear secretion, we developed a mathematical model of ion and water transport in acinar cells. It incorporates conservation of mass and electroneutrality within the cell and the bathing solutions, kinetic models of Na+-K+-ATPase, the NKCC1 and KCC1 co-transporters, and passive fluxes of ions, non-electrolytes and water. Cell-volume-sensitive reciprocal regulation of the activities of NKCC1 and KCC1 is represented with two empirical functions that vary with cell volume. The effects of muscarinic stimulation on apical Cl- and K+ permeabilities were also included. Simulations were done with identical apical and serosal bath compositions corresponding to those used in experiments on isolated acinar cells.
Results::
The model predicts RVI and regulatory volume decrease responses similar to measurements in isolated acinar cells, as well as secretion-induced cell shrinkage. In the latter case, the activation of NKCC1 supplies K+ and Cl- that balances the apical efflux, resulting in persistent decrease in cell volume. Simulation of inhibition of carbachol-induced increases in apical K+ and Cl- channel permeabilities resulted in attenuated cell shrinkage responses as observed in isolated acinar cells.
Conclusions::
The ability of the model to predict responses to hypertonic cell shrinkage and muscarinic stimulation suggests that a common signaling pathway may mediate the increase in NKCC1 that occurs in both cases.
Keywords: lacrimal gland • ion transporters • computational modeling