Using heparan sulfate octadecasaccharide (18-mer) as a multi-target agent to protect against sepsis.
Yi-En LiaoYongmei XuKatelyn ArnoldFuming ZhangJine LiRani SellersChaoyin YinVijayakanth PagadalaAnna Marie InmanRobert J LinhardtDing XuRafal PawlinskiKatelyn ArnoldPublished in: Proceedings of the National Academy of Sciences of the United States of America (2023)
Sepsis is a lethal syndrome manifested by an unregulated, overwhelming inflammation from the host in response to infection. Here, we exploit the use of a synthetic heparan sulfate octadecasaccharide (18-mer) to protect against sepsis. The 18-mer not only inhibits the pro-inflammatory activity of extracellular histone H3 and high mobility group box 1 (HMGB1), but also elicits the anti-inflammatory effect from apolipoprotein A-I (ApoA-I). We demonstrate that the 18-mer protects against sepsis-related injury and improves survival in cecal ligation and puncture mice and reduces inflammation in an endotoxemia mouse model. The 18-mer neutralizes the cytotoxic histone-3 (H3) through direct interaction with the protein. Furthermore, the 18-mer enlists the actions of ApoA-I to dissociate the complex of HMGB1 and lipopolysaccharide, a toxic complex contributing to cell death and tissue damage in sepsis. Our study provides strong evidence that the 18-mer mitigates inflammatory damage in sepsis by targeting numerous mediators, setting it apart from other potential therapies with a single target.
Keyphrases
- septic shock
- acute kidney injury
- intensive care unit
- oxidative stress
- cell death
- mouse model
- anti inflammatory
- inflammatory response
- metabolic syndrome
- radiation therapy
- lps induced
- adipose tissue
- binding protein
- cell proliferation
- radiation induced
- immune response
- skeletal muscle
- small molecule
- insulin resistance
- amino acid