Dabigatrán evita la apoptosis mediada por lipopolisacárido en el pez cebra mediante un mecanismo independiente de la trombina

Endotoxemia is a feature of sepsis pathogenesis and has also been found to mediate the pathophysiology of multiple inflammatory conditions. In this work, we use a lipopolysaccharide (LPS) induced endotoxemia model in zebrafish to identify novel mediators of LPS toxicity. We performed transcriptomic studies on LPS-treated larvae, followed by in silico analysis, which revealed associations between the signatures of LPS-treated embryos and those of drugs involving diverse pathways. In parallel, we performed an in vivo screen using >1,500 FDA-approved compounds and identified multiple novel small molecules that reduced inflammation and prevented LPS toxicity. We focused on the direct thrombin inhibitor dabigatran, which was identified through both the in vivo and in silico analyses. We found that dabigatran co-administration significantly reduced the expression of inflammatory cytokines and completely protected zebrafish from endotoxemic death due to LPS. Surprisingly, we found that this protection occurs in prothrombin mutant fish, proving that protection from endotoxemia occurs independently of the anticoagulant function of dabigatran. We additionally found that dabigatran administration significantly decreased nitric oxide production and apoptosis compared to LPS treatment alone, suggesting possible mechanisms by which protection from endotoxemia is achieved. In summary, we identify several novel small molecules that prevent LPS-induced endotoxemia and show that one such small molecule, dabigatran, exerts a thrombin-independent effect on nitric oxide production and apoptosis. This and the other identified small molecules warrant further exploration in inflammatory conditions including sepsis.

Resumen tomado de PubMed (NCBI) para el registro citado, en el idioma original. La versión de referencia es la de la publicación original.

El resumen se deja sin traducir para conservar la redacción original de los autores.

En un modelo de endotoxemia por LPS en pez cebra se cribaron in vivo más de 1500 compuestos aprobados por la FDA y se analizaron in silico perfiles transcriptómicos. Dabigatrán, identificado por ambas vías, redujo significativamente las citocinas inflamatorias y protegió por completo de la muerte por LPS. La protección se mantuvo en mutantes de protrombina y se acompañó de menor producción de óxido nítrico y apoptosis. Los autores consideran justificada su exploración en sepsis y otras afecciones inflamatorias.

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