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.
Highlights
High-mobility group box-1 (HMGB1) is an evolutionarily conserved, chromatin-binding protein expressed in virtually all types of cells[5]
To assess the response and time-dependent changes in inflammatory mediators across the Pediatric Acute Liver Failure (PALF) non-survivors and three survivor sub-groups (APAPo + NAC, non-APAPo + NAC, and non-APAPo non-NAC) (Fig. 1), we assayed a number of mediators that represent most of the major inflammatory and immune pathways
This analysis suggested that the standard statistical analysis of mediators, singly or as a group, may be of limited use for characterizing and predicting patient outcomes, because of potentially more complex, non-linear, and non-intuitive interactions among inflammatory mediators
Summary
High-mobility group box-1 (HMGB1) is an evolutionarily conserved, chromatin-binding protein expressed in virtually all types of cells[5]. As an extension of our previous work[8,9], Translational Systems Biology modeling methodology developed for biologically complex and dynamic conditions[10,11] was applied to correlate biomarkers with clinical outcomes as well as identify potential therapeutic targets in PALF. Recapitulation of these findings using an in vitro model of isolated HC exposed to APAP ± NAC was used to create a bedside-to-bench translational platform for further investigation
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