Design of anti-inflammatory heparan sulfate to protect against acetaminophen-induced acute liver failure
- 18 March 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 12 (535)
- https://doi.org/10.1126/scitranslmed.aav8075
Abstract
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 N-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 N-acetyl cysteine loses protection. Therefore, 18-mer-HP may offer a potential therapeutic advantage over N-acetyl cysteine for late-presenting patients. Synthetic HS provides a potential approach for the treatment of APAP-induced ALF.Keywords
Funding Information
- National Institutes of Health (GM102137)
- National Institutes of Health (HL094463)
- National Institutes of Health (GM128484)
- National Institutes of Health (DK111958)
- National Institutes of Health (HL125371)
- National Institutes of Health (CA207717)
- National Institutes of Health (AR070179)
- Pharmaceutical Research and Manufacturers of America Foundation
- American Foundation for Pharmaceutical Education
- Eshelman Innovation Institute
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