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The role of toll-like receptors in the pathogenesis of liver diseases
Petrášek, Jan ; Jirsa, Milan (advisor) ; Tlaskalová - Hogenová, Helena (referee) ; Červinková, Zuzana (referee)
Identifikační záznam: PETRÁŠEK, Jan. ÚLOHA TOLL-LIKE RECEPTORŮ V PATOGENEZI JATERNÍCH ONEMOCNĚNÍ. [The role of toll-like receptors in the pathogenesis of liver diseases]. Praha, 2010. 198s., Disertační práce. Univerzita Karlova v Praze, 1. lékařská fakulta, Laboratoř Experimentální Hepatologie IKEM. Vedoucí práce: Milan Jirsa. Abstrakt Společným jmenovatelem nejčastějších onemocnění jater je aktivace mechanismů vrozené imunity, které přispívají k rozvoji zánětu a poškození jaterního parenchymu. Klíčovou úlohu v rozvoji jaterního poškození hrají Toll-like receptory, jejichž charakterizace v posledním desetiletí vedla přehodnocení patofyziologie některých jaterních onemocnění. Předkládaná práce studuje význam alelických variant v genech kódujících proteiny Toll-like receptorové signální kaskády a mezibuněčné signalizace v patogenezi alkoholické nemoci jater, přináší nový pohled na probiotika v léčbě nealkoholické steatohepatitidy a nové poznatky o protizánětlivém působení interferonů I. typu u některých jaterních chorob. Abstract Recent reports suggest that majority of chronic and acute liver diseases share a significant degree of liver inflammation and injury attributable to innate immunity, activated through Toll-like receptors. Detailed characterization of Toll-like receptor sigaling cascades in the last...
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Enterohepatic circulation of bilirubin
Zelenka, Jaroslav ; Vítek, Libor (advisor) ; Entlicher, Gustav (referee) ; Červinková, Zuzana (referee)
Bilirubin is a main physiological product of heme degradation possessing important antioxidant and antiinflammatory properties. On the other hand, it could be neurotoxic during severe unconjugated hyperbilirubinemia combined with insufficiency of blood-brain barrier (neonatal jaundice). It is secreted from the body via bile and is further metabolized in the intestine. Part of the substance is reduced to urobilinoids, part is adsorbed to the intestinal content and some part could be reabsorbed back to the systemic circulation. This enterohepatically and enterosystemically circulating fraction varies in size depending on the rate of bilirubin secretion, solubility in the intestine and intensity of its intestinal metabolism. Under specific circumstances, EHC and ESC may significantly increase serum and bile bilirubin levels and influence physiological as well as pathological processes occuring in the body. Among the most important is the protective elevation of UCB levels in Gilbert syndrome subjects and dangerous increase in severity of neonatal jaundice. In the presented thesis, the mechanisms affecting EHC and ESC of bilirubin and tools for further research in BP metabolism were investigated. The solubility of intestinal UCB is strongly decreased by addition of divalent cations. However, such approach to...
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Study of signal systems with special focus on the role of nitric oxide: gene expression, regulation and pharmacological modulation in hepatocytes and adipocytes
Kutinová Canová, Nikolina ; Farghali, Hassan (advisor) ; Červinková, Zuzana (referee) ; Martásek, Pavel (referee)
Nitric oxide (NO) is involved in surprising array of vital physiological and pathophysiological phenomena. The expression of nitric oxide synthases, endothelial (eNOS) and inducible (iNOS), was demonstrated in rat liver and white adipose tissue among others. Therefore, the goals of the present thesis were to provide in vitro data about NO in the liver and white adipose tissue and to assess: 1) the effects of selective immunosuppressive drugs, cyclosporin A (CsA) and tacrolimus (FK 506), and nonspecific and specific iNOS inhibitors on NO production and iNOS expression during endotoxemic insult using primary rat hepatocyte culture; 2) spontaneous NO production under various culture conditions with comparison of its influence on functional status of hepatocytes in conventional cell culture and in hepatocyte bioreactors; 3) effects of S-nitroso-N-acetyl penicillamine (SNAP), D- galactosamine (D-GalN), lipopolysaccharide (LPS), LPS+D-GalN and thapsigargin (TG), a selective inhibitor of a sarco-endoplasmic reticulum-Ca2+ -ATPase, on apoptotic/necrotic markers in relation to NO production; 4) the effect of LPS on lipolysis in relation to iNOS stimulation; and 5) the interplay between NO production and β3-adrenoreceptor (β3- AR)/cAMP pathway on lipolysis in rat epididymal adipocyte culture. We found that CsA, FK...
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The study of the changes of hepatocyte energy metabolism: the effect of oxidative stress and triiodthyronine
Endlicher, René ; Červinková, Zuzana (advisor) ; Kalous, Martin (referee) ; Rauchová, Hana (referee)
Changes of energy metabolism of hepatocytes: The effect of oxidative stress and triiodothyronine Liver is a vital organ performing numerous essential functions. Due to its position in the blood circulation, liver is the first organ incessantly exposed to a great number of toxic substances. Respiratory chain located in mitochondria is a frequent target of toxic action of these substances. There are various mechanisms that participate in hepatocyte damage, nevertheless the most important mechanism of hepatotoxic effect is oxidative stress induced by increased production of free radicals. Impact of oxidative stress on hepatocytes is very complex and still not fully elucidated. The aim of my thesis was to investigate the effect of oxidative stress on energy metabolism of rat hepatocytes using isolated hepatocytes and isolated mitochondria. We evaluated the effect of oxidative stress on the activity of mitochondrial enzymes and function of mitochondrial permeability transition pore (MPTP), respectively. Opening of this pore induces activation of apoptotic and necrotic processes. Our results document selective action of oxidative stress on the activity of various mitochondrial enzymes. Tert-butylhydroperoxide (t-BHP) causes significant inhibition of NADH-dependent substrates, while oxidation of...
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Characterization of Mitochondrial Respiratory Chain Defects Using DNA Microarrays
Čížková, Alena ; Kmoch, Stanislav (advisor) ; Kováč, Ladislav (referee) ; Červinková, Zuzana (referee)
A mitochondrion is a organelle under nuclear and mitochondrial genetic control and its maintence requires a nucleo-mitochnodrial cross-talk. Better understanding of mitochondrial pahologies using various gene expression techniques. This thesis presents the implementation and application of microarray technology for identification of disease causing genes in respiratory chain disorders, expecially in patients with ATP synthase deficiency of nuclear origin. The introduction to this thesis provides an overview of mitochondrial structure and biogenesis, respiratory chain complexes and their disorders as well as different types of microarrays. A study of mitochondrial ATP synthase deficiency represents the major experimental part of this thesis and is accordingly that were used in further studies centered on characterization of inherited metabolic disorders. This is documented in positional cloning of patientes with lysosomal storage disorders - mucopolysaccharidosis IIIC.
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Immune Reactivity of Hepatic T Lymphocytes and Their Role in Pathogenesis of Liver Diseases
Carey, Ivana ; Vítek, Libor (advisor) ; Urbánek, Petr (referee) ; Červinková, Zuzana (referee)
The interaction of different pathogens with systemic and liver immune system is suggested an important factor in pathogenesis of various liver diseases. The variable aspects of this interaction and different immune system patways were subject of the present thesis. The ultimate goal of the present thesis was to investigate the reactivity of the local and systemic immune system against different disease related antigens and to demonstrate their participation in liver diseases and liver damage pathogenesis. Chronic hepatitis B infection, chronic hepatitis C infection and drug-induced liver damage were investigeted by 7 different studies using ex-vivo and in-vitro methods. In general, chronic liver diseases are associated with increased oxidative stress. Due to this fact, the role bilirubin, a potent endogenous antioxidant, was also analysed. The results of presented studies demonstrate clearly active participation of immune system to the pathogenesis of liver diseases, its direct involvement in liver damage and its effect on outcome of disease. The protective role of bilirubin in oxidative stress was confirmed. In conclusion, the results of all presented studies in this thesis illustrate the role of systemic as well as liver based immune system as a crucial player in the pathogenesis of liver...
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