Know-how and research interest
Liver disease, especially when progressed to advanced fibrosis or cirrhosis represents a major cause of death. More recently, hepatic fibrosis has been redefined as a highly dynamic process involving fibrogenesis, matrix degradation, angiogenesis and metabolic and immunological mechanisms. Abnormal remodeling of the hepatic sinusoidal vasculature represents a hallmark cirrhosis. Thus, the development of new treatment options to improve the structural (matrix), functional (synthesis), and hemodynamic (vascular) abnormalities in liver cirrhosis represents an important unmet clinical need. Portal hypertension (PH) is defined as an elevated pressure in the portal venous system that may cause severe complications such as formation of gastroesophageal varices, variceal bleeding, development of ascites, bacterial translocation and infections, hepatic encephalopathy, systemic vasodilation, and hyperdynamic circulation. Increased intrahepatic vascular resistance is the hallmark of sinusoidal PH with hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs) playing pivotal roles in this process. HSCs transform from quiescent, vitamin A-storing subendothelial cells to myofibroblast-like cells endowed with contractile, proinflammatory, and fibrogenic properties. Pathological angiogenesis is involved in the development of increased portal inflow and pressure as well as the formation of portosystemic collaterals and is closely linked to hepatic fibrogenesis. My lab thus focuses on the characterization of all these structural, functional, vascular and hemodynamic abnormalities characterizing advanced liver disease in order to develop novel treatment strategies.
Hepatic microenvironment in liver disease focusing on fibrogenesis, angiogenesis, sinusoidal vascular remodeling and portal hypertension.
Methods and Techniques of the research group
- CCl4 model (toxic cirrhosis with portal hypertension): Due to repetitive administration of the hepatotoxic agent carbon tetrachloride (CCl4) micronodular liver fibrosis, cirrhosis and portal hypertension are induced
- PPVL model (isolated portal hypertension without cirrhosis): Due to partial portal vein ligation (PPVL) a sudden increase in portal pressure is induced that affects splanchnic hemodynamics, angiogenesis and hyperdynamic circulation as seen in prehepatic portal hypertension without hepatic dysfunction.
- BDL model (cholestatic cirrhosis with hepato-pulmonary syndrome): The common bile duct is ligated and resected resulting in progressive cholestasis and inflammation ultimately leading to fibrosis and cirrhosis. BDL animals also develop a hepato-pulmonary syndrome (HPS) characterized by intrapulmonary vasodilation and right-left shunting resulting in impaired oxygenation.
- NASH model: different diets, usually characterized by high-fat (HFD) or methionine-choline deficient (MCD) content are administered in order to induce metabolic liver disease that may progress to fibrosis and cirrhosis with portal hypertension
- Measurement of portal pressure by invasive vascular cannulation.
- Measurement of systemic hemodynamics, heart rate and arterial pressures by invasive cannulation of the femoral or carotid artery
- Measurement of portosystemic shunting (PSS) by injection of radioactive or colored microspheres in the portal vein or the splenic pulp followed by the measurement of the fractions of microspheres retrieved from the capillary beds of the lung and the liver.
- Measurement of splanchnic arterial and portal venous blood flow by using non-constrictive perivascular ultrasound flow probes.
- Measurement of central venous pressure by invasive cannulation of the internal jugular vein.
- Isolation of primary parenchymal and non-parenchymal liver cells
1. „Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats“ by Reiberger T, Angermayr B,Schwabl P, Rohr-Udilova N, Mitterhauser M, Gangl A, Peck-Radosavljevic M. Journal of Hepatology 2009; 51: 865-873
2. "Nebivolol deteriorates portal hemodynamics in cirrhotic rats by increasing splanchnic blood flow” by Reiberger T, Payer BA, , Schwabl P, Horvatits T, Jäger B, Hummel T, Mitterhauser M, Trauner M, Fuhrmann V, Angermayr B, Peck-Radosavljevic M. Liver International 2013;33(4):561-568
3. „The effects of sorafenib on the portal hypertensive syndrome in patients with liver cirrhosis and hepatocellular carcinoma – a pilot study“ by Pinter M, Sieghart W, Reiberger T, Rohr-Udilova N, Ferlitsch A, Peck-Radosavljevic M. Alimentary Pharmacology and Therapeutics 2012;35(1):83-91
4. “An orthotopic mouse model of hepatocellular carcinoma with underlying liver cirrhosis” by Reiberger T, Chen Y, Ramjiawan RR, Hato T, Fan C, Samuel R, Roberger S, Huang P, Lauwers GY, Zhu AX, Bardeesy N, Jain RK, Duda DG. Nature Protocols 2015;10(8):1264-74.
5. “The FXR agonist PX20606 ameliorates portal hypertenision by targeting vascular remodeling and sinusoidal dysfunction” by Schwabl P, Hambruch E, Seeland BA, Hayden H, Wagner M, Garnys L, Strobel B, Schubert TL, Riedl F, Mittereggger D, Burnet M, Starlinger P, Oberhuber G, Deuschle U, Rohr-Udilova N, Podesser BK, Peck-Radosavljevic M, Reiberger T, Kremoser C, Trauner M. J Hepatol 2017; 66(4):724-733
6. “The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats” by Schwabl P, Brusilovskaya K, Supper P, Bauer D, Königshofer P, Riedl F, Hayden H, Fuchs CD, Stift J, Oberhuber G, Aschauer S, Bonderman D, Gnad T, Pfeifer A, Uschner FE, Trebicka J, Rohr-Udolova N, Podesser BK, Peck-Radosavljevic M, Trauner M, Reiberger T. Sci Rep. 2018 Jun 19;8(1):9372
7. „Animal models of portal hypertension“ by Königshofer P, Brusilovskaya K, Schwabl P, Reiberger T. Biochim Biophys Acta Mol Basis Dis. 2019 May1;1865(5):1019-1030
8. “Vascular Targets for the Treatment of Portal Hypertension” by Brusilovskaya K, Königshofer P, Schwabl P, Reiberger T. Semin Liver Dis. 2019 Nov;39(4):483-501.
9. “Invasive Hemodynamic Characterization of the Portal-hypertensive Syndrome in Cirrhotic Rats” by Köngshofer P, Brusilovskaya K, Schwabl P, Podesser BK, Trauner M, ReibergerT. J Vis Exp. 2018 Aug 1;(138):57261. doi: 10.3791/57261.
10. „Soluble guanylyl cyclase stimulation and phosphodiesterase-5 inhibition improve portal hypertension and reduce liver fibrosis in bile duct-ligated rats” by Brusilovskaya K, Königshofer P, Lampach D, Szodl A, Supper P, Bauer D, Beer A, Stift J, Timelthaler G, Oberhuber G, Podesser BK, Seif M, Zinober K, Rohr-Udilova N, Trauner M, Reiberger T, Schwabl P. United European Gastroenterol J. 2020 Sep2:205064062094414. doi: 10.1177/205064062094414.