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 regar...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5967712?pdf=render |
| _version_ | 1828930250894999552 |
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| author | Johannes Maximilian Ludwig Yuling Zhang Walee Chamulitrat Wolfgang Stremmel Anita Pathil |
| author_facet | Johannes Maximilian Ludwig Yuling Zhang Walee Chamulitrat Wolfgang Stremmel Anita Pathil |
| author_sort | Johannes Maximilian Ludwig |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T00:30:00Z |
| format | Article |
| id | doaj.art-883d5eec93ec4b56b3bac453d6fd3024 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T00:30:00Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-883d5eec93ec4b56b3bac453d6fd30242022-12-21T23:24:54ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01135e019783610.1371/journal.pone.0197836Anti-inflammatory properties of ursodeoxycholyl lysophosphatidylethanolamide in endotoxin-mediated inflammatory liver injury.Johannes Maximilian LudwigYuling ZhangWalee ChamulitratWolfgang StremmelAnita PathilAIM: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.http://europepmc.org/articles/PMC5967712?pdf=render |
| spellingShingle | Johannes Maximilian Ludwig Yuling Zhang Walee Chamulitrat Wolfgang Stremmel Anita Pathil Anti-inflammatory properties of ursodeoxycholyl lysophosphatidylethanolamide in endotoxin-mediated inflammatory liver injury. PLoS ONE |
| title | Anti-inflammatory properties of ursodeoxycholyl lysophosphatidylethanolamide in endotoxin-mediated inflammatory liver injury. |
| title_full | Anti-inflammatory properties of ursodeoxycholyl lysophosphatidylethanolamide in endotoxin-mediated inflammatory liver injury. |
| title_fullStr | Anti-inflammatory properties of ursodeoxycholyl lysophosphatidylethanolamide in endotoxin-mediated inflammatory liver injury. |
| title_full_unstemmed | Anti-inflammatory properties of ursodeoxycholyl lysophosphatidylethanolamide in endotoxin-mediated inflammatory liver injury. |
| title_short | Anti-inflammatory properties of ursodeoxycholyl lysophosphatidylethanolamide in endotoxin-mediated inflammatory liver injury. |
| title_sort | anti inflammatory properties of ursodeoxycholyl lysophosphatidylethanolamide in endotoxin mediated inflammatory liver injury |
| url | http://europepmc.org/articles/PMC5967712?pdf=render |
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