HMGB1 is a Central Driver of Dynamic Pro-inflammatory Networks in Pediatric Acute Liver Failure induced by Acetaminophen
Autor: | Robert H. Squires, Derek Barclay, Estella M. Alonso, Yoram Vodovotz, Timothy R. Billiar, Ruben Zamora, Jinling Yin, Mike A. Leonis, Richard L. Simmons, Qi Mi |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Male lcsh:Medicine Pharmacology Cohort Studies 0302 clinical medicine HMGB1 Protein Child lcsh:Science Mice Knockout Multidisciplinary biology Analgesics Non-Narcotic humanities 3. Good health medicine.anatomical_structure Hepatocyte Child Preschool medicine.symptom Chemical and Drug Induced Liver Injury medicine.drug Adolescent Primary Cell Culture Context (language use) Inflammation chemical and pharmacologic phenomena HMGB1 Article 03 medical and health sciences Mediator medicine Animals Humans Acetaminophen business.industry lcsh:R Infant Liver Failure Acute In vitro Mice Inbred C57BL 030104 developmental biology Cell culture biology.protein Hepatocytes lcsh:Q Drug Overdose business 030217 neurology & neurosurgery Biomarkers |
Zdroj: | Scientific Reports, Vol 9, Iss 1, Pp 1-11 (2019) Scientific Reports |
ISSN: | 2045-2322 |
DOI: | 10.1038/s41598-019-42564-5 |
Popis: | 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. |
Databáze: | OpenAIRE |
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