The response to injury, in liver and in other systems is fibrosis. Chronic or recurrent liver injury leads to hepatic fibrosis and ultimately cirrhosis, with both intra and extra hepatic complications which include impaired hepatocellular function and portal hypertension. The key pathogenic event in this process is transition of resident perisinusoidal cells termed hepatic stellate cells (Ito or stellate cells) from a quiescent to an """"""""activated"""""""" state. This process is characterized by production of increased amounts of extracellular matrix and de novo expression of smooth muscle alpha actin, the latter characteristic consistent with their transformation to myofibroblasts. We have recently demonstrated that contractility is a further prominent feature of the activated phenotype, elicited in particular by the endothelins, a group of 21 ammo acid peptides known primarily for their vasoactive properties. Moreover, we have shown that in injured liver preproendothelin-1 mRNA levels are elevated. During the last granting period, we demonstrated that the cellular source of endothelin-1 (ET-1) during liver injury is (in contrast to predicted) the hepatic stellate cell rather than the hepatic endothelial cell. Moreover, we showed that the mechanism of this shift is largely due to upregulation of the enzyme that converts precursor ET-1 to the mature peptide, endothelin converting enzyme-1 (ECE-1). This identifies ECE-1 as central component in the regulation of ET during liver injury. Finally, we demonstrated that inhibition of ET action in the liver with a mixed ET receptor antagonist, partially inhibited the stellate cell fibrogenic response to injury. Collectively, the data indicate that increased production of ET in liver plays a central role in liver injury, contributing to both stellate cell activation and fibrogenesis. This model, in which ET is a key element has substantial relevance to other forms of wound healing. The overall focus of this program is to understand pathobiology of endothelins in disease;
the specific aims of the current proposal are to explore the regulation of endothelins in liver fibrosis in vivo. Toward this goal we will (1) examine regulation of ECE-1 by elements important in the wound healing response such as TGF-beta1 and extracellular matrix (2) characterize ET receptor modulation (3) investigate ECE-1 transcriptional and translational control (4) and in experimental liver injury, determine whether inhibition of ECE-1 inhibits stellate cell activation, hepatic fibrosis or intrahepatic resistance typical of portal hypertension. 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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