Ursodeoxycholyl lysophosphatidylethanolamide protects against CD95/FAS-induced fulminant hepatitis

• Verfasst von: Utaipan, Tanyarath [VerfasserIn]
• Verfasst von: Gan-Schreier, Hongying [VerfasserIn]
• Verfasst von: Pathil-Warth, Anita [VerfasserIn]
• Verfasst von: Stremmel, Wolfgang [VerfasserIn]
• Verfasst von: Chamulitrat, Walee [VerfasserIn]
• Titel: Ursodeoxycholyl lysophosphatidylethanolamide protects against CD95/FAS-induced fulminant hepatitis
• Verf.angabe: Tanyarath Utaipan, Ann-Christin Otto, Hongying Gan-Schreier, Warangkana Chunglok, Anita Pathil, Wolfgang Stremmel, and Walee Chamulitrat
• E-Jahr: 2017
• Jahr: 2017/08/01
• Umfang: 9 S.
• Fussnoten: Gesehen am 31.10.2018
• Titel Quelle: Enthalten in: Shock
• Ort Quelle: Hagerstown, Md. : Lippincott, Williams & Wilkins, 1994
• Jahr Quelle: 2017
• Band/Heft Quelle: 48(2017), 2, Seite 251-259
• ISSN Quelle: 1540-0514
• DOI: doi:10.1097/SHK.0000000000000831
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 158248211X

Abstract

ABSTRACT: Increased activation of CD95/Fas by Fas ligand in viral hepatitis and autoimmunity is involved in pathogenesis of fulminant hepatitis and liver failure. We designed a bile-acid phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE with LPE containing oleate at the sn-1) as a hepatoprotectant that was shown to protect against fulminant hepatitis induced by endotoxin. We herein further assessed the ability of UDCA-LPE to prevent death receptor CD95/Fas-induced fulminant hepatitis. C57BL/6 mice were intravenously administered with CD95/Fas agonistic monoclonal antibody (Jo-2) with or without 1 h pretreatment with 50 mg/kg UDCA-LPE. Jo-2 administration caused massive hepatocyte damage as seen by histology, and this was associated with a significant decrease in hepatic phosphatidylcholine (PC), lysoPC, and lysophosphatidylethanolamine levels. By histology, UDCA-LPE pretreatment improved hepatocyte damage and restored the loss of these phospholipids in part by a mechanism involving an inhibition of cytosolic phospholipaseA2 expression. Accordingly, Jo-2 treatment increased hepatic expression of cleaved caspase 8, caspase 3, and poly (ADP-Ribose) polymerase-1, and on the other hand decreased that of anti-apoptotic cellular FLICE-inhibitory protein. UDCA-LPE pretreatment was able to reverse all these changes. Moreover, UDCA-LPE attenuated inflammatory response by lowering the levels of Jo-2-induced proinflammatory cytokines TNF-α, IL-6, and IL-1β in liver and serum. UDCA-LPE was also able to decrease the levels of stimulated Th1/Th17 cytokines in Jo-2-primed isolated splenocytes. Taken together, UDCA-LPE exhibited potent anti-inflammatory effects against CD95/Fas-induced fulminant hepatitis.