Mechanisms for transcapillary transport-from molecules to clinical application

Capillaries are highly permeable to water and small solutes but very restrictive towards protein. This arrangement is necessary to maintain fluid equilibrium between plasma and tissue. There is a slow transfer of protein to supply tissues with e.g. import ant bioactive molecules. How the transport of fluid and molecules takes place is, surprisingly, still a controversial issue. With the present project I aim to investigate how transcapillary transport is accomplished. First, I focus on macromolecular trans port: Is it by vesicular transport (transcytosis) or across pores? The transport characteristics of genetically modified mice that lack endothelial caveolae, and thus are incapable of transcytosis will be studied. Furthermore, specific macromolecular (alb umin) transcytotic uptake will be blocked by using a specific antibody. Second, I focus on fluid and small solute transport in a clinical situation (peritoneal dialysis, PD): Is fluid transport from peritoneum by way of lymphatics or by capillary reabsorp tion (Starling equilibrium)? To adress this issue I will measure the gradients that govern the Starling equilibrium in a chronic PD model. Why does patients on long-term PD develop morphological and functional changes eventually leading to change of dialy sis therapy? To adress whether this is related to the low-grade inflammation induced by PD, a chronic PD rat model will be employed and proinflammatory cytokines will be measured in the peritoneal tissues. Furthermore, to adress the same issue, an antiinf lammatory substance (heparin) will be added to the fluid during PD in rats while assessing the transport characteristics. This project has a translational character with important implications for drug delivery and states of perturbed microvascular permea bility. It also may lead to better prescription of dialysis dose and understanding of why patients on chronic peritoneal dialysis develop morphological and functional changes.