A mathematical model of the volume, pH, and ion content regulation in reticulocytes. Application to the pathophysiology of sickle cell dehydration.

We developed a mathematical model of the reticulocyte, seeking to explain how a cell with similar volume but much higher ionic traffic than the mature red cell (RBC) regulates its volume, pH, and ion content in physiological and abnormal conditions. Analysis of the fluxbalance required by reticulocytes to conserve volume and composition predicted the existence of previously unsuspected Na(+)-dependent Cl- entry mechanisms. Unlike mature RBCs, reticulocytes did not tend to return to their original state after brief perturbations. The model predicted hysteresis and drift in cell pH, volume, and ion contents after transient alterations in membrane permeability or medium composition; irreversible cell dehydration could thus occur by brief K+ permeabilization, transient medium acidification, or the replacement of external Na+ with an impermeant cation. Both the hysteresis and drift after perturbations were shown to depend on the pHi dependence of the K:Cl cotransport, a major reticulocyte transporter. This behavior suggested a novel mechanism for the generation of irreversibly sickled cells directly from reticulocytes, rather than in a stepwise, progressive manner from discocytes. Experimental tests of the model's predictions and the hypothesis are described in the following paper.