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Koch, Elke (2006): Influence of Atrial Natriuretic Peptide on inflammatory pathways in the lung. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

The cardiovascular hormone ANP is known to exert anti-inflammatory properties in macrophages and endothelial cells. This work provides new insight into the inflammatory signalling pathways influenced by the ANP in the lung. For these purposes, the effects of ANP on both alveolar epithelial cells and a model of LPS-induced lung inflammation were characterized. In alveolar epithelial cells, ANP was shown to inhibit the activation of two major transcription factors, NF-kB and AP-1, in response to TNFa. Astonishingly, this did not result in a reduced expression of the adhesion molecule ICAM-1. ANP was also capable to diminish the activation of AP-1 and NF-kB in lung tissue in vivo using a mouse model of LPS-induced septic shock. The inhibition of NF-kB activation was caused by a delayed phosphorylation and subsequent degradation of IkBa. In addition, ANP treatment elevated total protein levels of IkBa. p38 MAPK and Akt are important mediators in LPS-induced signalling. We demonstrated an activation of these kinases in lung tissue in response to i.p. LPS challenge. ANP treatment was able to lessen this activation. Furthermore, exclusive ANP treatment resulted in an increased p38 MAPK activation, which might contribute to the observed impact on other pathways. ICAM-1 expression was not impaired in whole lung tissue. ANP strongly decreased TNFa serum levels dose-dependently, but had only a slight effect on TNFa tissue levels. Interestingly, TNFa mRNA expression was not significantly reduced. Taken together this work demonstrates that ANP is able to diminish several important inflammatory pathways which are involved in the development of acute respiratory distress syndrome in LPS-induced sepsis.