Changes in the homeostasis of human red blood cells during capillary transits

In this and the next paper of this series we apply the red cell model introduced in the previous paper to investigate the changes in RBC homeostasis during capillary transits and over the full circulatory lifespan of the cells. These are topics inaccessible to direct experimentation but rendered mature for a modelling approach by recent findings and by a large body of apparently unrelated early results which robustly constrain the parameter space offering the opportunity for an in depth study of the mechanisms involved. Capillary transit times vary between 0.5 and 1.5s during which the red blood cells squeeze and deform in the capillary stream transiently opening stress-gated PIEZO1 channels, creating minuscule quantal changes in RBC ion contents and volume. Widely accepted early views originally based on results from experimentally shear-stressed red cells suggested that quantal changes generated during capillary transits add up over time to generate the documented changes in RBC density during their long circulatory lifespan, the quantal hypothesis. Applying the new PIEZO1 extension of the RBC model (RCM) introduced in the previous paper we investigated in detail the changes in homeostatic variables that may be expected during single capillary transits resulting from transient PIEZO1 channel activation. The predicted quantal volume changes were infinitesimal in magnitude, biphasic in nature, and essentially irreversible within inter-transit periods. A sub-second transient PIEZO1 activation triggered a sharp swelling peak followed by a much slower recovery period towards lower-than-baseline volumes. The peak response was caused by net CaCl2 and fluid gain via PIEZO1 channels driven by the steep electrochemical inward Ca2+ gradient. The ensuing dehydration followed a complex time-course with sequential, but partially overlapping contributions by KCl loss via Ca2+-activated Gardos channels, PMCA mediated calcium extrusion and chloride efflux by the Jacobs-Steward mechanism. The change in relative cell volume predicted for single capillary transits was below 10-4, an infinitesimal volume change incompatible with a functional role in capillary flow. The biphasic response predicted by the RCM appears to conform to the quantal hypothesis, but whether its cumulative effects could account for the documented changes in density during RBC senescence required an investigation of the effects of myriad transits over the full period of circulatory lifespan, the subject of the next paper of this series.