Liver cirrhosis gradually changes the structure and/or function of many other tissues, including blood vessels, muscle, spleen, intestine, kidney, lung, and brain. These alterations contribute to the multiple, extra-hepatic manifestations of cirrhosis, including cutaneous spider telangectases, cachexia, increased intestinal permeability, ascites and the hepatorenal syndrome, the portopulmonary syndrome, and hepatic encephalopathy. The extra-hepatic manifestations of cirrhosis cause much of the morbidity and mortality that results from liver damage, and thus, have been major targets for palliative therapy in cirrhotic patients. Clinical and experimental data indicate that alterations in portal venous blood flow precede the extra-hepatic sequelae of cirrhosis. Portal hypertension and portal-systemic shunting of blood result from changes that occur along hepatic sinusoids during repair/remodeling responses that are evoked by chronic liver injury. Activation of hepatic stellate cells to myofibroblasts and hepatic accumulation of these and other types of fibroblasts play key roles in this process because these myofibroblastic cells (MF) produce vasoactive factors and matrix molecules that reconfigure the sinusoidal architecture and alter hepatic blood flow. Recently, we discovered that liver MF produce Hedgehog (Hh) ligands and release these factors in microparticles (MPs). To date, we have detected Hh-containing MP in blood and bile. These findings have potential relevance to the pathogenesis of the extrahepatic sequelae of cirrhosis because Hh ligands are potent morphogens. Our HYPOTHESIS is that liver injury promotes the inclusion of Hh ligands in MPs that are shed from certain types of liver cells. This permits distribution of liver-derived factors to distant sites where they initiate signaling in resident Hh-responsive target cells and, induce remodeling of extra-hepatic tissues, contributing to the systemic manifestations of cirrhosis. This project Aims to:
Specific Aim 1. Characterize Hh-containing MPs generated during liver injury.
This aim will tests the hypothesis that MPs derived from different liver cell types exhibit qualitative and quantitative differences in Hh pathway components.
Specific Aim 2. Determine the role of liver-derived MPs in inducing the extrahepatic sequelae of cirrhosis.
This aim will test whether liver-derived MPs elicit expression of Hh target genes and thereby alter the phenotypes of progenitor cells that become dysfunctional during cirrhosis. In conclusion, the successful accomplishment of proposed aims will help us to understand MPs signaling during liver cirrhosis and potentially create a new target particle for drug development. ? ? ?
