Hepatic fibrosis is the consequence of most types of chronic liver diseases (CLDs) and the common-endpoint cirrhosis represents one of the most common causes of death in the Western world. Currently, there are no effective therapies to treat liver fibrosis in patients in which the causative agent cannot be removed (e.g. patients after antiviral treatment with successful eradication of chronic hepatitis C virus infection) and mortality rates still remain unacceptably high. Considering these epidemiological data, the socioeconomic impact of liver cirrhosis is extraordinary. Liver cirrhosis was traditionally regarded as a “point-of-no-return” end-stage disease. More recently, hepatic fibrosis has been redefined as a highly dynamic process involving fibrogenesis, matrix degradation, angiogenesis and metabolic/hormonal mechanisms. Portal hypertension (PHT) is defined as an elevated pressure in the portal venous system may cause severe complications such as formation of gastroesophageal varices, variceal bleeding, development of ascites, occurrence of bacterial translocation, hepatic encephalopathy, systemic vasodilation, and hyperdynamic circulation are related to PHT. Increased intrahepatic vascular resistance is the hallmark of sinusoidal PHT with hepatic stellate cells (HSCs) playing a pivotal role in this process. HSCs transform from quiescent, vitamin A-storing subendothelial cells to myofibroblast-like cells endowed with contractile, proinflammatory, and fibrogenic properties. The sinusoidal endothelium is distinguished by openings (fenestrations) that, together with discontinuities in the basement membrane, are essential for proper permeability through this unique low resistance/low pressure microvascular network. Accordingly, matrix deposition within the space of Disse and closure of endothelial fenestrations – processes that together underlie sinusoidal capillarization - impede the rapid exchange of solutes between the sinusoidal space and hepatocytes, causing increased resistance to portal blood flow and PHT. In addition, the process of capillarization of intrahepatic sinusoids as found in cirrhotic livers may impair hepatic metabolism and may influence cellular and humoral signaling by altered vascular permeability. In summary, several structural, functional, hemodynamic, and abnormalities can be found in cirrhotic livers which may be all considered when assessing potential therapeutic targets for reversing liver fibrosis and sinusoidal remodeling.
Methods & Technique
Research experience in labor animal care, isolated rat liver perfusion, liver cell isolation, hepatocyte-couplets culture, confocal life-cell microscopy, surface fluorescence measurements, IF microscopy.
Vienna Hepatic Experimental Hemodynamic (HEPEX) Lab: Mouse and rat models of liver fibrosis, mouse and rat models of biliary cirrhosis, mouse and rat models of non-cirrhotic portal hypertension, hemodynamic measurements of splanchnic and portal blood flow, porto-systemic shunting, intrapulmonary shunting, and systemic and portal pressure.
Vienna Hepatic Hemodynamic Laboratory: hepativ-venous pressure gradient, right-heart catheterization, transjugular liver biopsy, hepatic vein blood sampling.
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