Paracrine signaling mediators of vascular endothelial barrier dysfunction in sepsis: implications for therapeutic targeting.

Vascular endothelial barrier disruption is a critical determinant of morbidity and mortality in sepsis. Whole blood represents a key source of paracrine signaling molecules inducing vascular endothelial barrier disruption in sepsis. This study analyzes whole-genome transcriptome data from sepsis patients' whole blood available in the NCBI GEO database to identify paracrine mediators of vascular endothelial barrier dysfunction, uncovering novel insights that may guide drug repositioning strategies. This study identifies the regulated expression of paracrine signaling molecules TFPI, MMP9, PROS1, JAG1, S1PR1, and S1PR5 which either disrupt or protect vascular endothelial barrier function in sepsis and could serve as potential targets for repositioning existing drugs. Specifically, TFPI (barrier protective), MMP9 (barrier destructive), PROS1 (barrier protective), and JAG1 (barrier destructive) are upregulated, while S1PR1 (barrier protective) and S1PR5 (barrier protective) are downregulated. Our observations highlight the importance of considering both protective and disruptive mediators in the development of therapeutic strategies to restore endothelial barrier integrity in septic patients. Identifying TFPI, MMP9, PROS1, JAG1, S1PR1, and S1PR5 as druggable paracrine regulators of vascular endothelial barrier function in sepsis could pave the way for precision medicine approaches, enabling personalized treatments that target specific mediators of endothelial barrier disruption to improve patient outcomes in sepsis.