Mechanisms for Transcapillary Transport - From Molecules to Clinical Application, 2009

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. important bioactive molecules. How the transport of fluid and molecules takes place is, surprisingly, still a controversial issue. With the present project I aimed at investigating how transcapillary transport is accomplished. First, I focused on macromolecular transport: 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 were studied. Furthermore, specific macromolecular (albumin) transcytotic uptake was blocked by using a specific antibody. Second, I focused 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 reabsorption (Starling equilibrium)? To adress this issue I measured the gradients that govern the Starling equilibrium in a chronic PD model. Why do patients on long-term PD develop morphological and functional changes eventually leading to change of dialysis therapy? To adress whether this was related to the low-grade inflammation induced by PD, a chronic PD rat model was employed and proinflammatory cytokines were measured in the peritoneal tissues. Furthermore, to adress the same issue, an antiinflammatory substance (heparin) was added to the fluid during PD in rats while assessing the transport characteristics. This project had a translational character with important implications for drug delivery and states of perturbed microvascular permeability. It also lead to better prescription of dialysis dose and understanding of why patients on chronic peritoneal dialysis develop morphological and functional changes.