Plasma biomarkers of liver injury and inflammation demonstrate a lack of apoptosis during obstructive cholestasis in mice

Benjamin L. Woolbright, Daniel J. Antoine, Rosalind E. Jenkins, Mary Lynn Bajt, B. Kevin Park, Hartmut Jaeschke*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Cholestasis is a pathological common component of numerous liver diseases that results in hepatotoxicity, inflammation, and cirrhosis when untreated. While the predominant hypothesis in cholestatic liver injury remains hepatocyte apoptosis due to direct toxicity of hydrophobic bile acid exposure, recent work suggests that the injury occurs through inflammatory necrosis. In order to resolve this controversy, we used novel plasma biomarkers to assess the mechanisms of cell death during early cholestatic liver injury. C57BI/6 mice underwent bile duct ligation (BDL) for 6-72 h, or sham operation. Another group of mice were given c-galactosamine and endotoxin as a positive control for apoptosis and inflammatory necrosis. Plasma levels of full length cytokeratin-18 (FL-K18), microRNA-122 (miR-122) and high mobility group box-1 protein (HMGB1) increased progressively after BDL with peak levels observed after 48 h. These results indicate extensive cell necrosis after BDL, which is supported by the time course of plasma alanine aminotransferase activities and histology. In contrast, plasma caspase-3 activity, cleaved caspase-3 protein and caspase-cleaved cytokeratin-18 fragments (cK18) were not elevated at any time during BDL suggesting the absence of apoptosis. In contrast, all plasma biomarkers of necrosis and apoptosis were elevated 6 h after Gal/End treatment. In addition, acetylated HMGB1, a marker for macrophage and monocyte activation, was increased as early as 12 h but mainly at 48-72 h. However, progressive neutrophil accumulation in the area of necrosis started at 6h after BDL. In conclusion, these data indicate that early cholestatic liver injury in mice is an inflammatory event, and occurs through necrosis with little evidence for apoptosis. (C) 2013 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)524-531
Number of pages8
JournalToxicology and Applied Pharmacology
Volume273
Issue number3
DOIs
Publication statusPublished - 15 Dec 2013

Keywords

  • Bile duct ligation
  • Apoptosis
  • Biomarkers
  • Cytokeratin-18
  • High mobility group box-1
  • microRNA-122
  • BILE-DUCT LIGATION
  • ACID-INDUCED APOPTOSIS
  • HEPATIC ISCHEMIA-REPERFUSION
  • PARENCHYMAL-CELL APOPTOSIS
  • CHROMATIN PROTEIN HMGB1
  • ONCOTIC NECROSIS
  • RAT HEPATOCYTES
  • ACETAMINOPHEN HEPATOTOXICITY
  • MOUSE MODEL
  • DEATH

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