The Exchange Across Capillary Walls

Co-workers, postdoc level and above: Anders Grubb Professor, Jan Tencer Associate Professor, Ola Carlsson Postdoc, Anders Wieslander Associate Professor, Bert-Inge Rosengren Postdoc, Daniele Venturoli Associate Professor, Omran Bakoush MD, PhD, Ole Torffvit Associate Professor

The cells of the body require a constant "internal milieu" provided by the microcirculation, across which small solutes, macromolecules and fluid are exchanged. Disturbances in the microcirculation can be seen during shock, inflammation, in oedematous conditions etc. The basic mechanisms responsible for the microvascular exchange are still not fully elucidated.

The present project is aimed at describing the physiology of the exchanges of fluid and solutes, especially macromolecules, across capillary endothelia. We are focusing on the exchange in the peritoneum during peritoneal dialysis (PD) and on transglomerular transport of proteins and mechanisms of proteinuria. We have demonstrated a bimodal size-selectivity of capillary walls and developed new equations for describing transvascular protein exchange across high-selectivity endothelial pathways (small pores) and low-selectivity pathways (large pores). We have shown an unchanged or a higher transcapillary protein passage in mice lacking endothelial vesicles (no transcytosis). Based on computer simulations, we proposed the existence of transendothelial water pathways, accounting for a large portion of the osmotic fluid flow occurring across the peritoneum during PD. These pathways, Aquaporin-1, were cloned by the Nobel Prize laureate (2003) P Agre.

With respect to glomerular transport, we have studied glomerular sieving of proteins and Ficoll in vivo as a function of molecular size, charge and of glomerular filtration rate (GFR). The glomerular small pore radius is slightly smaller (35-40Å) than that determined using Ficoll (~48Å).

The present project has a number of clinical as well as basic science implications. The research has increased our understanding of the mechanisms responsible for the transport of proteins across vascular walls. The three-pore model of peritoneal transport has resulted in a computer model, by which it is possible to predict peritoneal transport alterations in various physiological conditions. The proteinuria research had lead to a deeper insight into the pathophysiology of the nephrotic syndrome.