Chronic injury to the liver and in other organs results in a wounding response characterized by fibrosis. This process is the integrated result of increased production of extracellular matrix proteins, tissue contraction, and thus disruption of the normal parenchymal architecture. The key cellular effectors in this process are termed myofibroblasts, cells which produce abundant extracellular matrix, and a multitude of cytokines and other factors that drive the fibrogenic process. The clinical result of ongoing hepatic fibrogenesis is cirrhosis, which results in both intra and extra hepatic complications that include impaired hepatpcellular function and portal hypertension. The effector myofibroblast in chronic liver injury is the hepatic stellate cell (Ito or stellate cells). From a mechanistic standpoint, one of the key events in injury is the transition of resident perisinusoidal stellate cells from a quiescent to an """"""""activated"""""""" cell. This process is characterized by production of increased amounts of extracellular matrix and de novo expression of smooth muscle a actin, the latter characteristic consistent with their transformation to myofibroblasts. We have demonstrated that contractility is a further prominent feature of the activated phenotype, elicited in particular by the endothelins, a group of 21 amino acid peptides known primarily for their vasoactive properties. Endothelins in chronic liver injury, and in other forms of wounding appear not only to be important in inducing contraction of myofibroblasts, but they appear to have pleotropic effects, including in fibrogenesis and proliferation. Thus, uncovering basic mechanisms of endothelin production is of critical importance. We have demonstrated that precursor endothelin-1 as well as the enzyme that converts precursor endothelin to the mature peptide, endothelin converting enzyme-1 (ECE-1) are upregulated in stellate cells after liver injury. This model, in which endothelin is a key element has substantial relevance to other forms of wound healing. The overall objective of the current program is to understand pathobiolqgy of endothelins in disease;
the specific aims of this proposal are to explore mechanisms of endothelin signaling in stellate cells in liver in- jury. Toward this goal we (1) examine mechanisms by which fibronectin species signal to stimulate endo- thelin-1 synthesis; (2) delineate mechanisms underlying TGF-p's effects on endothelin-1 synthesis, and (3) identify key elements of the endothelin signaling cascade that lead to cellular contraction in activated stellate cells. These studies have direct relevance to human liver disease and will lead to new approaches for the treatment of hepatic fibrosis and portal hypertension as well as other forms of fibrosing injury.
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