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DAMPs and sterile inflammation in drug hepatotoxicity

  • Runkuan Yang
  • Tor Inge Tonnesseen
Review Article
  • 75 Downloads

Abstract

Drug hepatotoxicity is the leading cause of acute liver failure (ALF) in the developed countries. The early diagnosis and treatment are still problematic, and one important reason is the lack of reliable mechanistic biomarkers and therapeutic targets; therefore, searching for new biomarkers and therapeutic targets is urgent. Drug hepatotoxicity induces severe liver cells damage and death. Dead and damaged cells release endogenous damage-associated molecular patterns (DAMPs). Increased circulating levels of DAMPs (HMGB1, histones and DNA) can reflect the severity of drug hepatotoxicity. Elevated plasma HMGB1 concentrations can serve as early and sensitive mechanistic biomarker for clinical acetaminophen hepatotoxicity. DAMPS significantly contribute to liver injury and inhibiting the release of DAMPs ameliorates experimental hepatotoxicity. In addition, HMGB1 mediates 80% of gut bacterial translocation (BT) during acetaminophen toxicity. Gut BT triggers systemic inflammation, leading to multiple organ injury and mortality. Moreover, DAMPs can trigger and extend sterile inflammation, which contributes to early phase liver injury but improves liver regeneration at the late phase of acetaminophen overdose, because anti-inflammatory treatment reduces liver injury at early phase but impairs liver regeneration at late phase of acetaminophen toxicity, whereas pro-inflammatory therapy improves late phase liver regeneration. DAMPs are promising mechanistic biomarkers and could also be the potential therapeutic targets for drug hepatotoxicity. DAMPs-triggered sterile inflammation contributes to liver injury at early phase but improves liver regeneration at later phase of acetaminophen hepatotoxicity; therefore, anti-inflammatory therapy would be beneficial at early phase but should be avoided at the late phase of acetaminophen overdose.

Graphical abstract

Keywords

Hepatotoxicity DAMPs Sterile inflammation Regeneration 

Abbreviations

ALF

Acute liver failure

MOF

Multiple organ failure

SIRS

Systemic inflammatory response syndrome

BT

Bacterial translocation

HMGB1

High mobility group box 1

NETs

Neutrophil extracellular traps

DAMP

Damage-associated molecular pattern

TLR

Toll-like receptor

APAP

Acetaminophen

MODS

Multiple organ dysfunction syndrome

LPS

Lipopolysaccharide

Notes

Author contributions

RKY designed and drafted the manuscript. TIT drafted and revised the manuscript.

Funding

This investigation was funded by South-Eastern Norway Regional Health Authority, Grant number 2013121.

Compliance with ethical requirements

This investigation has complete compliance with ethical standards.

Conflict of interest

The authors declare that they have no conflicts of interest.

Informed consent

Not applicable for a review article.

Ethical approval

Not applicable for a review article.

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Copyright information

© Asian Pacific Association for the Study of the Liver 2018

Authors and Affiliations

  1. 1.Department of Emergencies and Critical CareOslo University HospitalOsloNorway
  2. 2.Department of Critical Care MedicineUniversity of Pittsburgh Medical SchoolPittsburghUSA
  3. 3.Institute of Clinical MedicineUniversity of OsloOsloNorway

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