@article{409f209b351142128aaa8b054496546b,
title = "HMGB1 is a Central Driver of Dynamic Pro-inflammatory Networks in Pediatric Acute Liver Failure induced by Acetaminophen",
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.",
author = "Ruben Zamora and Derek Barclay and Jinling Yin and Alonso, {Estella M} and Leonis, {Mike A.} and Qi Mi and Billiar, {Timothy R.} and Simmons, {Richard L.} and Squires, {Robert H.} and Yoram Vodovotz",
note = "Funding Information: This work was supported by a Multi-Center Group to Study Acute Liver Failure in Children (NIH/NIDDK grant UO1 DK072146). We thank the collaborative effort of the following current and former principal and co-investigators of the Pediatric Acute Liver Failure Study (by site): University of Pittsburgh: Robert H. Squires MD, Benjamin L. Shneider MD; Cincinnati Children{\textquoteright}s Hospital: John Bucuvalas MD and Mike Leonis MD PhD; Lurie Children{\textquoteright}s Hospital of Chicago (Chicago): Estella Alonso MD; University of Texas Southwestern: Norberto Rodriguez-Baez MD; Seattle Children{\textquoteright}s Hospital: Karen Murray MD and Simon Horslen MB ChB; Children{\textquoteright}s Hospital Colorado (Aurora): Michael R. Narkewicz MD; St Louis Children{\textquoteright}s Hospital: David Rudnick MD PhD and Ross W. Shepherd MD; University of California at San Francisco: Philip Rosenthal MD; Hospital for Sick Children (Canada): Vicky Ng MD; Riley Hospital for Children (Indianapolis): Girish Subbarao MD; Emory University: Rene Romero MD; Children{\textquoteright}s Hospital of Philadelphia: Elizabeth Rand MD and Kathy Loomes MD; Kings College-London (England): Anil Dhawan MD; Birmingham Children{\textquoteright}s Hospital (England): Dominic Dell Olio MD and Deirdre A. Kelly MD; Texas Children{\textquoteright}s Hospital: Saul Karpen MD PhD, Mt. Sinai Medical Center: Nanda Kerkar MD; University of Michigan: M. James Lopez MD PhD; Children{\textquoteright}s Hospital Medical Center (Boston): Scott Elisofon MD and Maureen Jonas MD; Johns Hopkins University: Kathleen Schwarz MD; Columbia University: Steven Lobritto MD. We would also like to thank Regina M. Hardison, Tamara Lee Haller, and Steven H. Belle from the Data Coordinating Center at the University of Pittsburgh and the dedicated research coordinators at each site. Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41598-019-42564-5",
language = "English (US)",
volume = "9",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}