Transforming growth factor beta has long been recognized as the central growth factor in the pathogenesis of fibrosis. In addition, Myofibroblasts, a cell with characteristics of both fibroblasts and smooth muscle cells, is thought to be the critical cell type in extracellular matrix deposition and fibrogenesis. TGF beta is known to induce the myofibroblast phenotype from fibroblasts in vitro. This ability to effect phenotypic modulation of fibroblasts, however, appears to be dependant on whether the fibroblasts are stretched at the time of their exposure to TGF beta. We propose that Transforming Growth Factor Beta, the prototypical fibrogenic cytokine, and mechanical stretch of fibroblasts act synergistically to promote Fibrogenesis. In our research we will test the following hypotheses: 1) Mechanical Stretch of fibroblasts and TGF beta interact to induce the myofibroblast phenotype in vitro. 2) Mechanical stretch will alter SMAD and MAP Kinase activation in response to TGFbeta. 3) Gene expression in response to both stretch and TGFbeta will be distinct from either alone. 4) TGFb and mechanical stretch will act synergistically to increase both the stiffness of the tissue as well as its contractile component. Experiments will be carried out using an artificial tissue (fibroblast-populated collagen matrix) as well as a strain device in which the matrix can be placed and exposed to mechanical stretch.
