DAMPs and sterile inflammation in drug hepatotoxicity
Runkuan Yang1,2, Tor Inge Tonnesseen3,4
1Department of Emergencies and Critical Care, Oslo University Hospital, Nydalen, PO Box 4950, 0424, Oslo, Norway. runkuanyang@gmail.com.
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.
Insights
Drug-induced liver injury is a major cause of acute liver failure. Damage-associated molecular patterns (DAMPs) are key biomarkers and potential therapeutic targets for drug hepatotoxicity.
Area of Science:
- Hepatology
- Toxicology
- Immunology
Background:
- Drug hepatotoxicity is a leading cause of acute liver failure (ALF) in developed nations.
- Early diagnosis and treatment of drug-induced liver injury remain challenging due to a lack of reliable mechanistic biomarkers and therapeutic targets.
- Severe liver cell damage and death during drug hepatotoxicity lead to the release of endogenous damage-associated molecular patterns (DAMPs).
Purpose of the Study:
- To investigate the role of DAMPs as mechanistic biomarkers and potential therapeutic targets in drug-induced hepatotoxicity.
- To explore the involvement of DAMPs, specifically HMGB1, in acetaminophen-induced liver injury and its associated systemic inflammation.
- To evaluate the impact of DAMPs and sterile inflammation on liver regeneration in acetaminophen overdose.
Main Methods:
- Analysis of circulating DAMPs (HMGB1, histones, DNA) as indicators of drug hepatotoxicity severity.
- Assessment of HMGB1's role in mediating gut bacterial translocation (BT) in acetaminophen toxicity.
- Investigation of DAMPs-triggered sterile inflammation's dual role in early liver injury and late-phase liver regeneration.
Main Results:
- Elevated plasma HMGB1 concentrations serve as an early and sensitive biomarker for clinical acetaminophen hepatotoxicity.
- DAMPs significantly contribute to liver injury, and inhibiting their release ameliorates experimental hepatotoxicity.
- HMGB1 mediates a substantial portion of gut bacterial translocation during acetaminophen toxicity, triggering systemic inflammation and multi-organ injury.
Conclusions:
- DAMPs are promising mechanistic biomarkers for drug-induced hepatotoxicity.
- DAMPs represent potential therapeutic targets for managing drug-induced liver injury.
- The timing of anti-inflammatory therapy is critical in acetaminophen overdose, being beneficial in the early phase but potentially detrimental to liver regeneration in the late phase.
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