Anti-inflammatory properties of ursodeoxycholyl lysophosphatidylethanolamide in endotoxin-mediated inflammatory liver injury

• Verfasst von: Ludwig, Johannes Maximilian [VerfasserIn]
• Verfasst von: Zhang, Yuling [VerfasserIn]
• Verfasst von: Chamulitrat, Walee [VerfasserIn]
• Verfasst von: Stremmel, Wolfgang [VerfasserIn]
• Verfasst von: Pathil-Warth, Anita [VerfasserIn]
• Titel: Anti-inflammatory properties of ursodeoxycholyl lysophosphatidylethanolamide in endotoxin-mediated inflammatory liver injury
• Verf.angabe: Johannes Maximilian Ludwig, Yuling Zhang, Walee Chamulitrat, Wolfgang Stremmel, Anita Pathil
• E-Jahr: 2018
• Jahr: May 24, 2018
• Umfang: 15 S.
• Fussnoten: Gesehen am 01.08.2018
• Titel Quelle: Enthalten in: PLOS ONE
• Ort Quelle: San Francisco, California, US : PLOS, 2006
• Jahr Quelle: 2018
• Band/Heft Quelle: 13(2018,5) Artikel-Nummer e0197836, 15 Seiten
• ISSN Quelle: 1932-6203
• DOI: doi:10.1371/journal.pone.0197836
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Acute liver failure
• Sach-SW: Chemokines
• Sach-SW: Inflammation
• Sach-SW: Inflammatory diseases
• Sach-SW: Liver diseases
• Sach-SW: Liver fibrosis
• Sach-SW: Mouse models
• Sach-SW: Nitric oxide
• K10plus-PPN: 1578163021
• K10plus-PPN:
  Universitätsbibliothek
• Lokale URL UB: Zum Volltext

Abstract

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.