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Proc Natl Acad Sci U S A ; 120(4): e2209528120, 2023 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-36649428

RESUMEN

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.


Asunto(s)
Endotoxemia , Proteína HMGB1 , Sepsis , Ratones , Animales , Proteína HMGB1/metabolismo , Apolipoproteína A-I , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Lipopolisacáridos , Heparitina Sulfato , Modelos Animales de Enfermedad
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