Role of stromal cells in normal and pathological tissue homeostasis

The focus of this application is to study how the extracellular matrix can influence transcapillary transport of water and protein. The aim of this specific project is to develop an in vitro model system of loose connective tissue which can work in close parallel to our in vivo experiments. The unifying concept of the separate projects 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 gen erate edema «actively» via a lowering of interstitial fluid pressure (Pif), in burn 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 Pif is due to perturbation of the cellular beta-1-integrins receptors towards structural components in the extracellular matrix. Thus, contrary to the common notion, alterations in extracellular matrix rather than at t he capillary wall are responsible for the rapidly forming edema in acute inflammation. We will develop further a spheroid model system of connective tissue that allows studies on contribution of individual integrins to Pif, and their response to inflammat ory stimuli. Also the importance of paracrine mechanisms for tumor angiogenesis and growth and the role of the stroma in carcinoma growth will be studied using metods from cellular and molecular biology. Our observations offer new understanding of the dif ficulties 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. Our studies point towards the lowering of Pif as an important and fundamental new pathophysiological mechanism also in septicaemia.