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Hartkorn, Andreas (2008): Different approaches to influence the ischemia/reperfusion injury of the liver. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

The ischemia/reperfusion injury (IRI) of the liver is a crucial pathologic process encountered in several clinical situations such as hemorrhagic shock, liver resection and transplantation which can lead to a significant amount of liver dys-function, liver non-function or possible mortality. Despite several promising interventions both pharmacological and physical in nature, including antioxidant therapy, storage manipulation and pre-conditioning, there are no clearly established methods available to prevent hepatic IRI at present. Only through a better understanding of the complex ischemia/reperfusion process one can find interesting targets to develop new strategies to combat this serious injury. This study is aimed at using products of natural and synthetic origin to examine their molecular function and their impact on hepatic IRI. The three approaches are as follows: a. EGb 761 (Dr. Willmar Schwabe Pharmaceuticals) is a standardized extract from the dried leaves of the Ginkgo biloba tree. Its different constituents drawn from the plant offer a wide range of approved medicinal applications.6 Due to its diverse molecular activities affecting the redox system, microcirculation, mitochondrial function to name a few, EGb 761 might be an interesting candidate to be challenged in the multifunctional IRI process. b. Dietary flavonoids have shown to have beneficial therapeutic effects, attributed mainly to their antioxidant capacity. Xanthohumol, the prominent flavonoid of the hop plant, Humulus lupulus L., and its metabolic derivative 3-Hydroxyxanthohumol, both posses promising antioxidant properties in vitro.10, 11 The IRI of the liver is a complex injury process driven by oxidative stress, in which these compounds might be interesting. c. Selective NF-κB inhibition in Kupffer cells using NF-κB decoy nanoparticles is an approach shown to be of great value in the model of warm IR by Dr. Florian Hoffmann in his recent Ph.D. thesis. The cold IR model used in this case was assigned as Kupffer cells are vigorously activated and as it is solely influenced by hepatic factors. Therefore, it is an appropriate model to specify the role of selective NF-κB targeting in the liver in the best possible way.