Role of TNFα and hepatic glutamine synthetase in pathogenesis of hepatic encephalopathy. Inaugural-Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf vorgelegt von Vitaly Pozdeev aus Pavlograd, USSR Düsseldorf, October 2018 aus dem Institut für Molekulare Medizin II der Heinrich-Heine-Universität Düsseldorf Gedruckt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf Berichterstatter: 1.Prof. Dr. Philipp Lang 2. Prof. Dr. Eckhard Lammert Tag der mündlichen Prüfung: 11.10.2018 (bitte bei der Abgabe Ihrer Dissertation noch offen lassen) (bitte bei der Abgabe Ihrer Dissertation noch offen lassen) ii Table of content Table of figures ........................................................................................................... vi List of tables .............................................................................................................. vii Abstract .................................................................................................................... viii Zusammenfassung ...................................................................................................... x Acknowledgment ....................................................................................................... xii List of abbreviations .................................................................................................. xiii 1. Introduction ............................................................................................................. 1 1.1 Liver anatomy. .................................................................................................. 1 1.1.1 Gross anatomy. ....................................................................................................... 1 1.1.2 Cellular anatomy. ..................................................................................................... 2 1.1.2.1 Parenchymal cells. ............................................................................................... 2 1.1.2.1.1 Hepatocytes. ...................................................................................................... 2 Ammonia and glutamine metabolism. ........................................................................................ 3 Blood protein synthesis. ............................................................................................................. 5 Drugs and xenobiotics metabolism. ........................................................................................... 5 Lipid metabolism. ........................................................................................................................ 6 Liver zonation. ............................................................................................................................ 7 1.1.2. Nonparenchymal cells. ........................................................................................... 7 1.1.2.2 Sinusoidal endothelial cells. ................................................................................. 7 1.1.2.3 Kupffer cells. ......................................................................................................... 9 1.1.2.4 Stellate cells. ...................................................................................................... 10 1.1.2.5 Dendritic cells. .................................................................................................... 10 1.1.2.6 Lymphocytes. ..................................................................................................... 11 NK cells. ................................................................................................................................... 11 NKT cells. ................................................................................................................................. 12 T cells. ...................................................................................................................................... 12 Th cells. ................................................................................................................................ 13 Cytotoxic T-cells. .................................................................................................................. 13 1.2 Liver damage .................................................................................................. 14 1.2.1 Chemokines and cytokines. ................................................................................... 14 Chemokines. ............................................................................................................................. 14 Cytokines. ................................................................................................................................. 15 Tumor necrosis factor. ......................................................................................................... 15 IL-6. ...................................................................................................................................... 16 Transforming growth factor-β. .............................................................................................. 17 iii 1.2.2 Infectious disease .................................................................................................. 18 1.2.2.1 HBV .............................................................................................................................. 18 1.2.2.2 HCV .............................................................................................................................. 18 1.2.3 Non-alcoholic fatty liver disease. ........................................................................... 19 1.2.4 Liver cirrhosis. ....................................................................................................... 19 1.2.5 Hepatic encephalopathy. ....................................................................................... 20 1.2.5.1 Symptoms. .................................................................................................................... 20 1.2.5.2 Pathogenesis. ............................................................................................................... 21 Protein nitration. ................................................................................................................... 25 RNA oxidation. ..................................................................................................................... 26 Zn homeostasis. ................................................................................................................... 27 Neuroinflammation. .............................................................................................................. 28 Blood brain barrier. ............................................................................................................... 29 Na-K-Cl co-transporter. ........................................................................................................ 30 Aquaporins. .......................................................................................................................... 31 1.2.5.3 Therapy ........................................................................................................................ 32 Nutrition. ............................................................................................................................... 32 Antibiotics. ............................................................................................................................ 33 Ammonia scavengers. .......................................................................................................... 33 L-ornithine l aspartate. ......................................................................................................... 34 Polyethilene glycol. .............................................................................................................. 34 Probiotics. ............................................................................................................................. 34 N-acetylcisteine. ................................................................................................................... 34 Albumin dialysis. .................................................................................................................. 35 Minocyclin. ............................................................................................................................ 35 1.3 Death receptor-mediated apoptosis and liver. ................................................. 35 1.3.1 CD95. .................................................................................................................... 36 Role in liver disease. ................................................................................................................ 37 1.3.2 TNFα. .................................................................................................................... 38 NF-kb activation. ....................................................................................................................... 39 Apoptosis. ................................................................................................................................. 40 1.3.3 TRAIL ...................................................................................................................