Date of Award


Degree Type


Degree Name

Master of Science




Dr. Andrew Leask

Second Advisor

Dr. Frank Beier

Third Advisor

Dr. Peter Chidiac


Activated adhesive signaling and overproduction of both endothelin-1 (ET-1) and connective tissue growth factor (CCN2) are key features of fibrosis. However, the possible interconnection between these mediators in fibrogenic responses in fibroblasts is unknown. My objective was to investigate the contribution of adhesion to the fibrotic response and determine the role of ET-1 and CCN2 in this process. I show using Real Time RT-PCR that adhesion induces pro-fibrotic markers including Ccn2, a-Smooth muscle actin (aSma), type I collagen and Et-1. This activity was at least partially impaired by addition of a specific ET receptor antagonist (bosentan). Furthermore, in normal human lung fibroblasts bosentan also impairs the ability of transforming growth factor (TGF)-β to induce a fibrotic phenotype, including CCN2 expression. Using Real Time RT-PCR and immunofluoresence I show that CCN2 at least partially mediates a tissue repair/remodeling program. These results suggest that adhesion of fibroblasts to matrix may contribute to the fibrotic response through the induction of pro-fibrotic gene expression, and that this may occur, in part, through ET-1 and CCN2.



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