Research ArticleLIVER FAILURE

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

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Science Translational Medicine  18 Mar 2020:
Vol. 12, Issue 535, eaav8075
DOI: 10.1126/scitranslmed.aav8075

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Greater safety for a familiar drug

The drug acetaminophen/paracetamol (APAP) is commonly available and generally safe, but an overdose of this drug can cause potentially lethal liver failure. Although approved treatment for an overdose is available, it is not always sufficient, depending on the amount and timing of APAP exposure. Arnold et al. identified a heparan sulfate octadecasaccharide (18-mer) that inhibits the main inflammatory signaling pathway involved in APAP-induced liver failure. In mouse models of APAP overdose, this 18-mer was more effective than current clinical treatment, even when given 3 hours after APAP exposure, suggesting its potential for clinical use.

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.

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