Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
Sci Transl Med. 2020 Mar 18;12(535). doi: 10.1126/scitranslmed.aav8075.
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.
对乙酰氨基酚（APAP）过量是导致美国和欧洲药物性急性肝衰竭（ALF）的主要原因。这种疾病的进展归因于高迁移率族蛋白 B1（HMGB1）释放引起的无菌性炎症，以及与晚期糖基化终产物受体（RAGE）的相互作用。因此，非常需要一种特异性、有效性和安全性的方法来中和 HMGB1 的促炎活性。在这里，我们发现硫酸乙酰肝素（HS）十八聚糖（18-mer-HP 或肝保护 18-mer）通过靶向 HMGB1/RAGE 轴显示出强大的肝保护作用。内源性 HS 蛋白聚糖，硫酸乙酰肝素蛋白聚糖-1，在小鼠和人类中对 APAP 过量反应而脱落。此外，纯化的硫酸乙酰肝素蛋白聚糖-1，而不是硫酸乙酰肝素蛋白聚糖-1 核心蛋白，与 HMGB1 结合，表明 HMGB1 与硫酸乙酰肝素蛋白聚糖的 HS 多糖侧链结合。最后，我们比较了 18-mer-HP 和 -乙酰半胱氨酸之间的保护效果，后者是治疗 APAP 过量的标准治疗方法。我们证明，在 APAP 致死剂量后 3 小时给予 18-mer-HP 是完全保护的；然而，-乙酰半胱氨酸的治疗失去了保护作用。因此，18-mer-HP 可能为晚期就诊的患者提供优于 -乙酰半胱氨酸的潜在治疗优势。合成 HS 为治疗 APAP 诱导的 ALF 提供了一种潜在的方法。
