Die Rolle des Chemokinrezeptors CXCR3 im Rahmen der akuten und chronischen Leberschädigung
Year: 2012
Type: dissertation
Abstract: Because of its anatomical localization, the liver plays a very important role during the immune response. It is enriched with various immune cell populations, i.e. macrophages, T-cells or NK-cells. In the same way further immune cells can be recruited from the peripheral blood, which is regulated by a complex chemokine ligand- receptor system. This study investigated the role of the chemokine receptor CXCR3 and its ligands CXCL4, CXCL9, CXCL10 and CXCL11 during acute and chronic liver diseases. Therefore in vivo experiments with CXCR3 knockout mice were applied and the obtained data were verified with human samples and further in vitro experiments. It could be shown that the chemokine receptor CXCR3 is essential for the recruitment of NK- and NKT- cells during the acute CCl4 induced liver injury. The reduced amount of these cells resulted in an augmented necrotic damage which was accompanied by an elevated intrahepatic HMGB1 concentration. This led to an enhanced infiltration of neutrophils into the liver and which than further increased the liver damage. In the second part of this study it was shown that the chemokine CXCL9 and its receptor CXCR3 are important mediators of murine and human HCV induced liver fibrosis. CXCR3 knockout mice developed an enhanced fibrosis, compared to wild type mice, which was associated with a reduced infiltration of IFN-γ producing T-cells. During human HCV induced liver fibrosis the intrahepatic CXCL9 concentration increased with ongoing fibrosis. Additionally it could be proven that the Chemokine CXCL9 acts antifibrotic on stellate cells in vitro. It was also shown that the chemokine CXCL4 and platelets are involved in chronic liver diseases. During human HCV induced fibrosis the platelets are in direct contact to the collagen fibrils and CXCL4 concentration increased with ongoing fibrosis. Additionally it could be proven that the Chemokine CXCL4 acts profibrotic on stellate cells in vitro. The results obtained in this study show an unexpected positive role of the chemokine receptor CXCR3 during acute toxic liver injury, which should be taken into account for future treatments with CXCR3 antagonists. There were also chemokine based antifibrotic pathways described, which could the first steps for potential antifibrotic therapies. Concluding it was proven that platelets play an important role during chronic liver diseases and could be a potential new target for the development of antifibrotic therapies.
Source: RWTH Publications (RWTH Aachen)
Author: Moreno Zaldivar, Mirko
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W6999749474