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L. C. Moore, W. C. Huang, C. Clausen, P. Brink, B. Walcott; Mathematical Model of Lacrimal Acinar Cell pH and Volume Regulation. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5302.
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The onset of water, K+, and Cl– secretion by stimulated lacrimal acinar cells (LAC) is associated with cell shrinkage, and increased activities of the Na+-K+-2Cl– cotransporter (NKCC1), and Na+-H+ (NHE1) and Cl–-HCO3– (AE) exchangers. These transporters pump Na+ and Cl– into the cell to maintain tear secretion. However, experiments in monolayers of cultured LAC have shown that LAC ion transport is relatively insensitive to inhibition of either the NHE1 or NKCC1 transporters, whereas inhibition of both transporters significantly reduces ion transport (Selvam, et al. Am J Physiol 293: C1412, 2007). We investigated whether this response pattern can be explained by interactions between the mechanisms of tear secretion, cell volume (CV) regulation and pH homeostasis.
We used a mathematical model of LAC ion and water transport which is based on mass conservation, electroneutrality constraints, and includes kinetic models of Na+-K+-ATPase, NKCC1, the K+-Cl– cotransporter (KCC), NHE1, AE, as well as representation of CO2 hydration, and passive fluxes of ions, non-electrolytes and water. The effects of muscarinic stimulation to enhance apical Cl– and K+ permeabilities and the activities of Na+-K+-ATPase, NHE1, and AE transporters are also included, as are the effects of CV changes on the NKCC1 and KCC transporters.
The model LAC cells secrete a high [K+] hypertonic solution with a composition that agrees with measurements. The model predicts increased NHE1 and AE ion transport when NKCC1 is blocked, and increased NKCC1 uptake when NHE1 is inhibited. In both cases, the compensatory changes involve reductions in cell [Cl–] which changes the driving force for the NKCC1 and AE exchangers. Also, inhibition of NHE reduces CV, and this results in upregulation of NKCC1 activity in the model.
These results suggest that interactions of the transporters involved in tear secretion, CV regulation and pH control are, in part, mediated by altered cytosolic Cl– levels and by regulatory resonses to changes in cell volume.
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