Ex-vivo perfusion of human liver tissue as model for pharmacological liver inury and hepatic steatosis

点击翻译按钮获取中文摘要

We were able to demonstrate that our perfusion system can mimic poisoning by acetaminophen ex vivo in human liver tissue specimen in the currently funded project. The system employed by us offers the advantage of using intact human liver tissue in a native architecture and cooperative cellular structure. Acetaminophen toxicity in the perfusion system reflected inter-individual variance from clinical observations in patients, which do not occur in vitro or in animal models. MicroRNA-122 release into the perfusate and mitochondrial damage were identified as early events in acetaminophen-induced liver injury. This again reflects the clinical situation in acetaminophen-induced acute liver failure.In the proposed follow up project the acetaminophen dose will be adapted to achieve 100 % poisoning rate. This will allow characterization of the system to analyze liver toxicity of unknown substances in the future. Thus we hope to identify individual, patient specific risk factors for acetaminophen-induced acute liver failure. Furthermore it will enable testing of established as well as experimental therapeutic approaches for acetaminophen-induced acute liver failure and to identify the involved cell types and molecular mechanisms. To this end, samples from the perfusate as well as from liver tissue will be collected and secretion as well as expression of markers for injury and for specific cell types will be assessed after acetaminophen dosage and either N-acetylcysteine dosage (established therapy) or application of thromboxane-synthase inhibitors (experimental therapy).The perfusion model will also be expanded for generation of liver steatosis, independent from characterization of acetaminophen toxicity in our system. In parallel to the world-wide obesity pandemic non-alcoholic fatty liver disease (NAFLD) is on the rise and is the most common chronic liver disease in industrialized countries by now. The basis for NAFLD is excess fat accumulation (steatosis) in the liver. Early processes of fat accumulation and subsequent liver injury are still incompletely understood or are largely based on in vitro models. In the human ex vivo perfusion model we can generate steatosis and will elucidate cellular and regulatory mechanisms of this process in the proposed project. In particular, we will be able to observe the early mechanisms of steatosis development and subsequent metabolic changes as well as behavior of non-parenchymal liver cells in human liver tissue in an intact cooperative cell structure. We expect novel insights into possible preventive or therapeutic approaches against NAFLD.