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Pathology of neonatal sepsis : discriminating survival and identifying new therapeutic targets

University of British Columbia

The global mortality rate in the neonatal period is far greater than in any other time in childhood. Sepsis is one of the most significant causes of neonatal death worldwide and therefore represents a critical research target moving forward. There is an urgent need for pathogen-agnostic prophylactics and interventions to prevent and treat neonatal sepsis, but the development of these has been slow and ineffective due to a fundamental knowledge-gap surrounding the pathology of the disease. Here we first developed a method for classifying cecal slurry challenged mouse pups into likely survivors or likely non-survivors to identify why some pups survive the sepsis model and others do not. We then examined the transcriptomes of likely survivors and likely non-survivors and identified arachidonic acid metabolism as key point of differentiation between the two groups. We validated these findings by showing the administration of exogenous arachidonic acid prior to challenge significantly improved survival its protective effect was ultimately due to improvements in vascular endothelial integrity via interactions with the angiopoietin-TIE2 axis. Combinatorial treatment of exogenous angiopoietin-1 and L-Arginine significantly reduced mortality and represents a promising new intervention moving forward.

Text

2021-04-22

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/77933

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/