The dynamic interstitial matrix and transcapillary exchange: Normal function and pathophysiology

The focus of this application is how the extracellular matrix can influence transcapillary transport of water and protein. The separate projects are closely related and cover studies from the level of single cells and organs to the organism. The unifying concept is the hypothesis that extracellular matrix can have an «active» role on transcapillary transport: We have demonstrated that in inflammation and burn injury the tissues generate edema «actively» via a lowering of interstitial fluid pressure, in b urn injury from -1 mmHg to as low as -150 mmHg, raising capillary net filtration pressure 150-300 times above control. In inflammation, we have demonstrated that the final and common step resulting in lowering of interstitial fluid pressure is due to pert urbation of the cellular beta1-integrin receptors towards structural components in the extracellular matrix. Thus, contrary to the common notion, alterations in extracellular matrix rather than at the capillary wall are responsible for the rapidly formin g edema in acute inflammation. The mechanisms involved will be studied using transgenic animals and methods adapted from cellular and molecular biology. Our observations offer new understanding of the difficulties of transport of cytostatic agents across the vasculature in cancers and at the same time provide new and mostly untested opportunities for facilitating such transcapillary transport in cancers. Furthermore, our studies point towards the lowering of interstitial pressure as an important and fund amental pathophysiological mechanism also in septicaemia. The hypothesis will be tested in vivo by direct measurement of transcapillary exchange using a range of methods including microdialysis, biophysical methods and mathematical modelling.