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DAMPs and sterile inflammation in drug hepatotoxicity

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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.

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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

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Funding

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

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Authors and Affiliations

  1. Department of Emergencies and Critical Care, Oslo University Hospital, Nydalen, PO Box 4950, 0424, Oslo, Norway

    Runkuan Yang & Tor Inge Tonnesseen

  2. Department of Critical Care Medicine, University of Pittsburgh Medical School, 3550 Terrace Street, Pittsburgh, PA, 15261, USA

    Runkuan Yang

  3. Institute of Clinical Medicine, University of Oslo, Blindern, 0316, Oslo, Norway

    Tor Inge Tonnesseen

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  1. Runkuan Yang
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RKY designed and drafted the manuscript. TIT drafted and revised the manuscript.

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Yang, R., Tonnesseen, T.I. DAMPs and sterile inflammation in drug hepatotoxicity. Hepatol Int 13, 42–50 (2019). https://doi.org/10.1007/s12072-018-9911-9

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