In the aftermath of the explosive inflammatory response characterizing acute lung injury, plasma fibrinogen extravasates through the disrupted alveolar wall into the airspace. It becomes polymerized to cross-linked fibrin by components of the coagulation cascade forming a provisional matrix. In response to peptide growth factors, angiogenesis factors, and haptotactic signals present within the provisional matrix, myofibroblasts and endothelial cells migrate into the airspace and form intraalveolar granulation tissue. Available data connect fibrin with the process of angiogenesis. Common to provisional matrix proteins are inherent functions which mediate cell adhesion and migration. In acute lung injury patients we have identified an 150kD angiogenesis factor which promotes endothelial cell adhesion and migration. That the 150kD protein shares such functions with proteins comprising the provisional matrix suggests that they may be structurally related. A strikingly unique feature of the 150kD protein not shared by other extracellular matrix proteins is its ability to simulate new vessel growth in the absence of inflammation. The ability to initiate angiogenesis suggests that this moiety is capable of modulating the endothelial cell phenotype from sedentary to migratory. We propose to examine our hypothesis by purifying the 150kD protein and examining its effect on expression of cell surface receptors which mediate capillary endothelial cell adhesion and migration. The second major objective of this proposal will focus on the changes in cell surface matrix receptor expression and function which accompany the change to a motility phenotype and which facilitate endothelial and function which accompany the change to a motility phenotype and which facilitate endothelial cell migration on fibrin, a major component of the provisional matrix. Recent investigations in our laboratory have implicated two key cell surface matrix receptors, alpha VBeta3 integrin and chondroitin sulfate proteoglycan as mediators of endothelial cell migration and invasion. In addition, peptide growth and differentiation factors are capable of modulating cell surface matrix receptors. Therefore, we will investigate the effects of peptide growth factors that have been closely associated with lung inflammation microvascular endothelial cell motility phenotype.
Showing the most recent 10 out of 70 publications
