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Keller, Melanie (2005): Cytoprotective and Anti-Inflammatory Properties of the Atrial Natriuretic Peptide during Ischemia/Reperfusion and Endotoxemia. Dissertation, LMU München: Fakultät für Chemie und Pharmazie



Ischemia-reperfusion injury (IRI), which is unavoidable in liver transplantation, is a multifactorial process that can cause non-function or dysfunction of the graft. These complications are the major cause for retransplantation and mortality. An understanding of the mechanisms involved in IRI is essential for the design of therapeutic strategies to prevent IRI and thus improve the outcome of liver transplantation. In recent years, the Atrial Natriuretic Peptide (ANP) has been demonstrated to posses potential in protection against IRI. Nevertheless, many questions remain to be answered about signaling pathways involved in ANP-mediated effects and the processes responsible for its protective properties. The isolated perfused rat liver is a well-investigated model for examination of treatment-mediated effects during ischemia and reperfusion (IR) in the liver. Using this setting, Kiemer et al. demonstrated that ANP-preconditioning increases the activity of p38 MAPK in isolated perfused livers during IR. Functional consequences of an activation of p38 MAPK are widely unknown. This protein kinase has been shown to participate in the regulation of cytoskeletal structures in various cells. Thus, our field of interest was to find a causal connection between ANP-mediated effects and possible cytoskeletal changes during IR in this model. In respect of IRI in the liver, ANP was evidenced to exhibit protective effects also in vivo, but so far nothing is known about signaling pathways responsible for this action. Apototic cell death in the liver during IR is discussed controversial and ANP was demonstrated to mediate anti-apoptotic effects in the isolated perfuse rat liver. We therefore aimed to determine whether ANP mediates effects in the liver in vivo regarding apoptotic death during IR. ANP has not only been shown to have protective properties in IRI but also anti-inflammatory effects in vitro. In previous studies we were able to show that ANP prevents TNF-α production in murine macrophages and whole human blood after LPS-stimulation. Moreover, we ddemonstrated that ANP also inhibits TNF-α-induced aactivation of NF-κB in human endothelial cells and reduces LPS-induced TNF-α secretion in Kupffer cells (KC). With regard to inflammatory processes during LPS-induced endotoxemia TNF-α has been demonstrated to be one of the prototypic pro-inflammatory cytokines mediating many of the immunopathological features of this disease. During sepsis endogenous ANP is suggested to be a regulatory mediator, as the level of its precursor Pro-ANP in blood from septic patients has been demonstrated to be an important rognostic marker for the outcome of sepsis. Another topic discussed in this work is therefore the disease pattern of sepsis. This life-threatening disorder results from a harmful host response to infection and is the leading cause of death for patients in intensive care units. Despite intensive research on the mechanisms involved in the fatal outcome of this disease, few is known about potential therapies preventing death of patients suffering from sepsis. Based on the knowledge of ANP-mediated protective effects during deleterious processes in IRI and its anti-inflammatory properties we therefore aimed to answer the following questions: 1. Does pretreatment with ANP cause cytoskeletal changes in the liver during IR in the isolated perfused rat liver? Which cell type is affected? What are the underlying signaling mechanisms for these changes? 2. Is apoptosis of liver cells during liver transplantation influenced by ANP? Which anti-apoptotic pathway is involved? 3. Are anti-inflammatory properties of ANP able to maintain survival after LPS-induced septic shock? How does ANP influence inflammatory processes during endotoxaemia?