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Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06 Podcast
Cytoprotective and Anti-Inflammatory Properties of the Atrial Natriuretic Peptide during Ischemia/Reperfusion and Endotoxemia

Cytoprotective and Anti-Inflammatory Properties of the Atrial Natriuretic Peptide during Ischemia/Reperfusion and Endotoxemia

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 02/06 vor 21 Jahren

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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?