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Generation of a Rat Model of Acute Liver Failure by Combining 70% Partial Hepatectomy and Acetaminophen

Generation of a Rat Model of Acute Liver Failure by Combining 70% Partial Hepatectomy and Acetaminophen

Published on: November 27, 2019

HMGB1 is a Central Driver of Dynamic Pro-inflammatory Networks in Pediatric Acute Liver Failure induced by

Ruben Zamora^1,2, Derek Barclay¹, Jinling Yin¹

¹Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA.

Scientific Reports

|April 14, 2019

Insights

High Mobility Group Box 1 (HMGB1) network connectivity differs between pediatric acute liver failure survivors and non-survivors. N-acetylcysteine (NAC) antagonizes pro-inflammatory HMGB1 signaling in non-survivors, promoting repair in survivors.

Area of Science:

Hepatology
Immunology
Biochemistry

Background:

Acetaminophen overdose (APAPo) is a leading cause of pediatric acute liver failure (PALF).
Inflammatory mediators play a critical role in PALF pathogenesis and outcomes.
High Mobility Group Box 1 (HMGB1) is implicated in inflammatory responses.

Purpose of the Study:

To investigate the role of HMGB1 in dynamic inflammatory networks in pediatric patients with acute liver failure.
To determine if HMGB1 network connectivity differs between survivors and non-survivors of PALF.
To explore the impact of N-acetylcysteine (NAC) on HMGB1 signaling in APAPo.

Main Methods:

Assayed inflammatory mediators in serial serum samples from PALF patients (survivors and non-survivors).
Utilized Dynamic Network Analysis (DyNA) to assess HMGB1 network connectivity.
Investigated hepatocyte (HC) damage in vitro using APAP + NAC treatment in wild-type and HMGB1-null mouse HC.

Main Results:

HMGB1 was a dominant mediator in inflammatory networks across all patient groups.
A threshold network complexity event at days 1-2 post-enrollment was associated with non-survival.
HMGB1 exhibited higher connectivity in non-survivors on days 2-3, while survivors showed no HMGB1 connections.
NAC treatment was associated with altered HMGB1 connectivity in APAPo patients.
In vitro studies showed HC HMGB1 recapitulated survivor network phenotypes and was altered in HMGB1-null HC.

Conclusions:

Differential HMGB1 network connectivity after day 2 is linked to PALF non-survival.
NAC antagonizes pro-inflammatory HMGB1 signaling in non-survivors and may promote anti-inflammatory/repair programs in survivors.
HC HMGB1 plays a crucial role in coordinating inflammatory responses in PALF, influencing patient outcomes.

Read full analysis

Abstract:

Acetaminophen (APAP) overdose (APAPo) is predominant in the NIH Pediatric Acute Liver Failure (PALF) Study. We assayed multiple inflammatory mediators in serial serum samples from 13 PALF survivors with APAPo + N-acetylcysteine (NAC, the frontline therapy for APAPo), 8 non-APAPo + NAC, 40 non-APAPo non-NAC, and 12 non-survivors. High Mobility Group Box 1 (HMGB1) was a dominant mediator in dynamic inflammation networks in all sub-groups, associated with a threshold network complexity event at d1-2 following enrollment that was exceeded in non-survivors vs. survivors. We thus hypothesized that differential HMGB1 network connectivity after day 2 is related to the putative threshold event in non-survivors. DyNA showed that HMGB1 is most connected in non-survivors on day 2-3, while no connections were observed in APAPo + NAC and non-APAPo + NAC survivors. Inflammatory dynamic networks, and in particular HMGB1 connectivity, were associated with the use of NAC in the context of APAPo. To recapitulate hepatocyte (HC) damage in vitro, primary C57BL/6 HC and HC-specific HMGB1-null HC were treated with APAP + NAC. Network phenotypes of survivors were recapitulated in C57BL/6 mouse HC and were greatly altered in HMGB1-null HC. HC HMGB1 may thus coordinate a pro-inflammatory program in PALF non-survivors (which is antagonized by NAC), while driving an anti-inflammatory/repair program in survivors.

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