Anti-inflammatory properties of ursodeoxycholyl lysophosphatidylethanolamide in endotoxin-mediated inflammatory liver injury
Aim: Endotoxin-mediated liver inflammation is a key component of many acute and chronic liver diseases contributing to liver damage, fibrosis and eventually organ failure. Here, we investigated ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), a synthetic bile acid-phospholipid conjugate rega...
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| Main Authors: | , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
May 24, 2018
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| In: |
PLOS ONE
Year: 2018, Volume: 13, Issue: 5 |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0197836 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1371/journal.pone.0197836 Verlag, kostenfrei, Volltext: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197836 
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| Author Notes: | Johannes Maximilian Ludwig, Yuling Zhang, Walee Chamulitrat, Wolfgang Stremmel, Anita Pathil |
| Summary: | Aim: Endotoxin-mediated liver inflammation is a key component of many acute and chronic liver diseases contributing to liver damage, fibrosis and eventually organ failure. Here, we investigated ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), a synthetic bile acid-phospholipid conjugate regarding its anti-inflammatory and anti-fibrogenic properties. Methods: Anti-inflammatory properties of UDCA-LPE were evaluated in a mouse model of D-galactosamine/lipopolysaccharide (GalN/LPS)-induced acute liver injury, LPS treated RAW264.7 macrophages and murine primary Kupffer cells. Furthermore, anti-inflammatory and anti-fibrotic effects of UDCA-LPE were studied on primary hepatic stellate cells (HSC) incubated with supernatant from LPS±UDCA-LPE treated RAW264.7 cells. Results: UDCA-LPE ameliorated LPS-induced increase of IL-6, TNF-α, TGF-β, NOX-2 in the GalN/LPS model by up to 80.2% for IL-6. Similarly, UDCA-LPE markedly decreased the expression of inflammatory cytokines IL-6, TNF-α and TGF-β as well as the chemokines MCP1 and RANTES in LPS-stimulated RAW 264.7 cells. Anti-inflammatory effects were also observed in primary murine Kupffer cells. Mechanistic evaluation revealed a reversion of LPS-activated pro-inflammatory TLR4 pathway by UDCA-LPE. Moreover, UDCA-LPE inhibited iNOS and NOX-2 expression while activating eNOS via phosphorylation of AKT and pERK1/2 in RAW264.7 cells. HSC treated with conditioned medium from LPS±UDCA-LPE RAW264.7 cells showed lower fibrogenic activation due to less SMAD2/3 phosphorylation, reduced expression of profibrogenic CTGF and reduced pro-inflammatory chemokine expression. Conclusion: In the setting of endotoxin-mediated liver inflammation, UDCA-LPE exerts profound anti-inflammatory and anti-fibrotic effect implying a promising potential for the drug candidate as an experimental approach for the treatment of acute and chronic liver diseases. |
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| Item Description: | Gesehen am 01.08.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0197836 |