The cardiovascular hormone ANP interferes with LPS-induced early inflammatory pathways in vitro and in vivo

Ladetzki-Baehs, Kathrin (2006): The cardiovascular hormone ANP interferes with LPS-induced early inflammatory pathways in vitro and in vivo. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

Altogether, we have proven that ANP mediated effects are diverse yet similar in different organs derived from endotoxemic mice and in isolated blood leukocytes. These ANP mediated interactions are proceeding at the onset of LPS-induced inflammation and sepsis. Primarily, we can clearly demonstrate that ANP preconditioning in endotoxemic mice yields TNF-alpha m-RNA reduction, determined in the spleen as well as in the liver. As investigated in whole liver tissue, ANP preconditioning mediates its beneficial effects by reducing LPS-induced transcription factor NF-kappaB activation. This reduction is caused by decreased phosphorylation of the NF-kappaB inhibitory factor IkappaBalpha, proximately leading to impaired degradation of IkappaBalpha protein. Thus, enhanced IkappaBalpha protein level in the cytosol prevent NF-kappaB translocation into the nucleus, and subsequently transcription factor activity and gene expression. These effects might be caused by or lead to the reduction in TNF-alpha gene expression, finally preventing liver failure. Secondly, besides the transcriptional regulation of TNF-aplha gene expression determined in spleen and liver tissue, we focused on ANP mediated effects in LPS stimulated murine and human blood derived leukocytes. Following LPS stimulation, we observed reduced total TNF-alpha protein levels as well as decreased TNF-alpha amounts on the cell-surface in ANP preconditioned blood leukocytes, respectively monocytes and neutrophils. These initial investigations indicate that the reduced TNF-alpha protein levels in leukocytes might either be evoked by interference of ANP in transcriptional or posttranscriptional processes. Eventually, due to its effects on key events of cell activation, such as the reduction of LPS-induced TNF-alpha expression, ANP may represent a promising beneficial autocrine substance in modulating early inflammatory signaling pathways.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: ANP, septic shock, inflammation, LPS
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 540 Chemie
• Fakultäten: Fakultät für Chemie und Pharmazie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 28. April 2006
• 1. Bericht­erstatter:in: Vollmar, Angelika