Design of anti-inflammatory heparan sulfate to protect against acetaminophen-induced acute liver failure

Acetaminophen/paracetamol (APAP) overdose is the leading cause of drug-induced acute liver failure (ALF) in the United States and Europe. The progression of the disease is attributed to sterile inflammation induced by the release of high mobility group box 1 (HMGB1) and the interaction with receptor...

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Published in:Science translational medicine 2020-03, Vol.12 (535)
Main Authors: Arnold, Katelyn, Xu, Yongmei, Sparkenbaugh, Erica M, Li, Miaomiao, Han, Xiaorui, Zhang, Xing, Xia, Ke, Piegore, Mark, Zhang, Fuming, Zhang, Xiaoxiao, Henderson, Mike, Pagadala, Vijayakanth, Su, Guowei, Tan, Lisi, Park, Pyong Woo, Stravitz, Richard T, Key, Nigel S, Linhardt, Robert J, Pawlinski, Rafal, Xu, Ding, Liu, Jian
Format: Article
Language:English
Subjects:
Acetaminophen
Advanced glycosylation end products
Core protein
Cysteine
Glycosylation
Heparan sulfate
HMGB1 protein
Inflammation
Lethal dose
Liver failure
Overdose
Paracetamol
Polysaccharides
Proteoglycans
Syndecan
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Summary:Acetaminophen/paracetamol (APAP) overdose is the leading cause of drug-induced acute liver failure (ALF) in the United States and Europe. The progression of the disease is attributed to sterile inflammation induced by the release of high mobility group box 1 (HMGB1) and the interaction with receptor for advanced glycation end products (RAGE). A specific, effective, and safe approach to neutralize the proinflammatory activity of HMGB1 is highly desirable. Here, we found that a heparan sulfate (HS) octadecasaccharide (18-mer-HP or hepatoprotective 18-mer) displays potent hepatoprotection by targeting the HMGB1/RAGE axis. Endogenous HS proteoglycan, syndecan-1, is shed in response to APAP overdose in mice and humans. Furthermore, purified syndecan-1, but not syndecan-1 core protein, binds to HMGB1, suggesting that HMGB1 binds to HS polysaccharide side chains of syndecan-1. Last, we compared the protection effect between 18-mer-HP and -acetyl cysteine, which is the standard of care to treat APAP overdose. We demonstrated that 18-mer-HP administered 3 hours after a lethal dose of APAP is fully protective; however, the treatment of -acetyl cysteine loses protection. Therefore, 18-mer-HP may offer a potential therapeutic advantage over -acetyl cysteine for late-presenting patients. Synthetic HS provides a potential approach for the treatment of APAP-induced ALF.
ISSN:1946-6234
1946-6242
1946-3242
DOI:10.1126/scitranslmed.aav8075