Amelioration of Bile Duct Ligation Induced Liver Injury by Lactoferrin: Role of Nrf2/HO-1 Pathway

Cholestatic liver injury results from impaired bile flow or metabolism and promotes hepatic inflammation and fibrogenesis. Toxic bile acids that accumulate in cholestasis induce apoptosis and contribute to early cholestatic liver injury, which is amplified by accompanying inflammation. The aim of the current study was to evaluate the role of the antiapoptotic caspase 8-homolog cellular FLICE-inhibitory (cFLIP) protein during acute cholestatic liver injury. Transgenic mice exhibiting hepatocyte-specific deletion of cFLIP (cFLIP−/−) were used for in vivo and in vitro analysis of cholestatic liver injury using bile duct ligation (BDL) and the addition of bile acids ex vivo. Loss of cFLIP in hepatocytes promoted acute cholestatic liver injury early after BDL, which was characterized by a rapid release of proinflammatory and chemotactic cytokines (TNF, IL-6, IL-1β, CCL2, CXCL1, and CXCL2), an increased presence of CD68+ macrophages and an influx of neutrophils in the liver, and resulting apoptotic and necrotic hepatocyte cell death. Mechanistically, liver injury in cFLIP−/− mice was aggravated by reactive oxygen species, and sustained activation of the JNK signaling pathway. In parallel, cytoprotective NF-κB p65, A20, and the MAPK p38 were inhibited. Increased injury in cFLIP−/− mice was accompanied by activation of hepatic stellate cells and profibrogenic regulators. The antagonistic caspase 8-homolog cFLIP is a critical regulator of acute, cholestatic liver injury. NEW & NOTEWORTHY The current paper explores the role of a classical modulator of hepatocellular apoptosis in early, cholestatic liver injury. These include activation of NF-κB and MAPK signaling, production of inflammatory cytokines, and recruitment of neutrophils in response to cholestasis. Because these signaling pathways are currently exploited in clinical trials for the treatment of nonalcoholic steatohepatitis and cirrhosis, the current data will help in the development of novel pharmacological options in these indications.

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Rolipram Attenuates Bile Duct Ligation–Induced Liver Injury in Rats: A Potential Pathogenic Role of PDE4

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.113.204933 ◽

2013 ◽

Vol 347 (1) ◽

pp. 80-90 ◽

Cited By ~ 20

Author(s):

Leila Gobejishvili ◽

Shirish Barve ◽

Katja Breitkopf-Heinlein ◽

Yan Li ◽

JingWen Zhang ◽

...

Keyword(s):

Bile Duct ◽

Liver Injury ◽

Bile Duct Ligation ◽

Pathogenic Role ◽

Duct Ligation

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Beneficial effects of cilostazol on liver injury induced by common bile duct ligation in rats: Role of SIRT1 signaling pathway

Clinical and Experimental Pharmacology and Physiology ◽

10.1111/1440-1681.13004 ◽

2018 ◽

Vol 45 (12) ◽

pp. 1341-1350 ◽

Cited By ~ 7

Author(s):

Soad L. Kabil

Keyword(s):

Bile Duct ◽

Liver Injury ◽

Common Bile Duct ◽

Signaling Pathway ◽

Bile Duct Ligation ◽

Common Bile Duct Ligation ◽

Beneficial Effects ◽

Duct Ligation

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Bid-mediated apoptosis does not contribute to cholestatic liver injury following bile duct ligation

Zeitschrift für Gastroenterologie ◽

10.1055/s-0029-1191793 ◽

2009 ◽

Vol 47 (01) ◽

Author(s):

P Nalapareddy ◽

S Schüngel ◽

MP Manns ◽

H Jaeschke ◽

A Vogel

Keyword(s):

Bile Duct ◽

Liver Injury ◽

Bile Duct Ligation ◽

Duct Ligation ◽

Cholestatic Liver Injury

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Faculty Opinions recommendation of A contradictory role of A1 adenosine receptor in carbon tetrachloride- and bile duct ligation-induced liver fibrosis in mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1345984.817085 ◽

2009 ◽

Author(s):

Jonathan A Dranoff

Keyword(s):

Carbon Tetrachloride ◽

Bile Duct ◽

Liver Fibrosis ◽

Adenosine Receptor ◽

Bile Duct Ligation ◽

A1 Adenosine Receptor ◽

Duct Ligation

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Vitamin A Supplementation Alleviates Extrahepatic Cholestasis Liver Injury through Nrf2 Activation

Oxidative Medicine and Cellular Longevity ◽

10.1155/2014/273692 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Guiyang Wang ◽

Peng Xiu ◽

Fu Li ◽

Cheng Xin ◽

Kewei Li

Keyword(s):

Bile Duct ◽

Liver Injury ◽

Liver Function ◽

Vitamin A ◽

Western Blotting ◽

Bile Duct Ligation ◽

Retinyl Palmitate ◽

Binding Activity ◽

Extrahepatic Cholestasis ◽

Duct Ligation

Aim. To investigate the role of vitamin A in liver damage induced by bile duct ligation (BDL) in rats.Methods. Thirty male Wistar rats were randomly divided into three groups: SHAM group, BDL group, and BDL + VitA group . The concentrations of retinol and retinyl palmitate in the liver were analyzed using HPLC, and liver function was evaluated by the level of TBIL, ALT, AST, and ALP in serum. Hepatic oxidative status was estimated by measuring T-SOD, CAT, GSH, MDA, and AOPP. Nrf2 expression was assessed using immunohistochemistry and western blotting, and EMSA was performed to determine Nrf2 DNA-binding activity. The expression of the downstream factors such as Ho1 and Nqo1 was also examined using immunohistochemistry and western blotting assays.Results. Vitamin A treatment restored levels of retinoids in liver, improved liver function, alleviated oxidative stress, and facilitated the translocation of Nrf2 to the nucleus in the experimental obstructive jaundice. Vitamin A was also found to increase the expression of Nrf2 downstream proteins such as Ho1 and Nqo1.Conclusion. Vitamin A was here found to ameliorate cholestatic liver injury. This effect may be related to the activation of Nrf2/ARE pathway in bile duct ligation rats.

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Targeting HMGB1/TLR4 axis and miR-21 by rosuvastatin: role in alleviating cholestatic liver injury in a rat model of bile duct ligation

Naunyn-Schmiedeberg s Archives of Pharmacology ◽

10.1007/s00210-018-1560-y ◽

2018 ◽

Vol 392 (1) ◽

pp. 37-43 ◽

Cited By ~ 5

Author(s):

Enas S. Nabih ◽

Omnyah A. El-kharashi

Keyword(s):

Bile Duct ◽

Liver Injury ◽

Rat Model ◽

Bile Duct Ligation ◽

Duct Ligation ◽

Cholestatic Liver Injury

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Cell-specific regulatory effects of CXCR2 on cholestatic liver injury

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00080.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. G773-G783 ◽

Cited By ~ 2

Author(s):

Takanori Konishi ◽

Rebecca M. Schuster ◽

Holly S. Goetzman ◽

Charles C. Caldwell ◽

Alex B. Lentsch

Keyword(s):

Bile Duct ◽

Liver Injury ◽

Liver Damage ◽

Chemokine Receptor ◽

Therapeutic Target ◽

Bile Duct Ligation ◽

Wild Type ◽

Neutrophil Accumulation ◽

Duct Ligation ◽

Cholestatic Liver Injury

The CXC chemokine receptor 2 (CXCR2) is critical for neutrophil recruitment and hepatocellular viability but has not been studied in the context of cholestatic liver injury following bile duct ligation (BDL). The present study sought to elucidate the cell-specific roles of CXCR2 on acute liver injury after BDL. Wild-type and CXCR2−/− mice were subjected BDL. CXCR2 chimeric mice were created to assess the cell-specific role of CXCR2 on liver injury after BDL. SB225002, a selective CXCR2 antagonist, was administrated intraperitoneally after BDL to investigate the potential of pharmacological inhibition. CXCR2−/− mice had significantly less liver injury than wild-type mice at 3 and 14 days after BDL. There was no difference in biliary fibrosis among groups. The chemokines CXCL1 and CXCL2 were induced around areas of necrosis and biliary structures, respectively, both areas where neutrophils accumulated after BDL. CXCR2−/− mice showed significantly less neutrophil accumulation in those injured areas. CXCR2Liver+/Myeloid+ and CXCR2Liver−/Myeloid− mice recapitulated the wild-type and CXCR2-knockout phenotypes, respectively. CXCR2Liver+/Myeloid+ mice suffered higher liver injury than CXCR2Liver+/Myeloid− and CXCR2Liver−/Myeloid+; however, only those chimeras with knockout of myeloid CXCR2 (CXCR2Liver+/Myeloid− and CXCR2Liver−/Myeloid−) showed reduction of neutrophil accumulation around areas of necrosis. Daily administration of SB225002 starting after 3 days of BDL reduced established liver injury at 6 days. In conclusion, neutrophil CXCR2 guides the cell to the site of injury, while CXCR2 on liver cells affects liver damage independent of neutrophil accumulation. CXCR2 appears to be a viable therapeutic target for cholestatic liver injury. NEW & NOTEWORTHY This study is the first to reveal cell-specific roles of the chemokine receptor CXCR2 in cholestatic liver injury caused by bile duct ligation. CXCR2 on neutrophils facilitates neutrophil recruitment to the liver, while CXCR2 on liver cells contributes to liver damage independent of neutrophils. CXCR2 may represent a viable therapeutic target for cholestatic liver injury.

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