Based on our previous and ongoing studies, fibronectin (FN) - a multifunctional dimeric glycoprotein in plasma, basal lamina, and connective tissue matrices - participates in host defense, maintenance of lung architecture, and collagen deposition. These multiple biologic roles are possible by virtue of FN binding via specific sites or domains to other structural macromolecules, to itself, and to receptor armed cells. While this general scheme is well established, the cellular and molecular basis of FN's interactions with cells and with connective tissue components is not presently understood, but is critical for elucidating FN's role in lung structure and function. We have developed and applied new methods over the past three years, including a library of domain specific anti-FN antibodies and fragments with defined biologic activity, as well as biochemical and morphologic techniques to critically evaluate the basis of FN's interactions with cells and organization of connective tissue matrices. These methods will now be applied to the following specific aims: 1) The role of FN in supramolecular organization and deposition of other pericellular matrix components, including collagen and glycosaminoglycans in fibroblast culture. 2) The mechanisms of pericellular matrix organization in fibroblast cultures. 3) The interaction of FN with cells in two contrasting models: the human alveolar macrophage, and cultured lung fibroblasts, using antibodies to the FN cell receptor and heterologous mixing experiments to determine the requirements for extracellular matrix formation by FN secreting cells. Together, our studies will lead to new knowledge and tools fundamental to understanding the basis of FN's biological activities, and help to clearly delineate FN's role in lung and other organ structure and function. This information will provide a rational basis for diagnostic and ultimately theraputic intervention in lung and other diseases characterized by abnormal organization of connective tissue matrices. A promising first step in this direction is our ability to inhibit collagen deposition in lung fibroblast cultures by selective inhibition of FN matrix formation.
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