Ladetzki-Baehs, Kathrin (2006): The cardiovascular hormone ANP interferes with LPS-induced early inflammatory pathways in vitro and in vivo. Dissertation, LMU München: Faculty of Chemistry and Pharmacy |
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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.
Item Type: | Theses (Dissertation, LMU Munich) |
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Keywords: | ANP, septic shock, inflammation, LPS |
Subjects: | 500 Natural sciences and mathematics 500 Natural sciences and mathematics > 540 Chemistry and allied sciences |
Faculties: | Faculty of Chemistry and Pharmacy |
Language: | English |
Date of oral examination: | 28. April 2006 |
1. Referee: | Vollmar, Angelika |
MD5 Checksum of the PDF-file: | 6295f4c16702d426d029fc2ca66cfcd3 |
Signature of the printed copy: | 0001/UMC 15700 |
ID Code: | 5838 |
Deposited On: | 12. Oct 2006 |
Last Modified: | 24. Oct 2020 09:14 |