Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Feng, Qingping

Abstract

Sepsis is a dysregulated immune response to infection and the leading cause of mortality globally, accounting for 11 million deaths in 2017. To date, no therapeutics are available to treat the underlying septic response. Previous research from our laboratory has shown that annexin A5 (Anx5) treatment increased survival by 40% in mice with endotoxemia, a model of sepsis. During sepsis, activated platelets release membrane fragments called extracellular vesicles (EVs) with externalization of phosphatidylserine to which annexin A5 binds with a high affinity. We hypothesized that annexin A5 will block the pro-inflammatory response induced by activated platelets and EVs in vascular endothelial cells under septic conditions. We showed that treatment with annexin A5 lowered expression of inflammatory cytokines and adhesion molecules induced by lipopolysaccharide (LPS)-activated platelets or EVs in endothelial cells. Furthermore, annexin A5 treatment improved endothelial integrity and reduced monocyte adhesion to endothelial cells in septic conditions. Our study shows that annexin A5 inhibits endothelial inflammation in septic conditions, suggesting its potential as a treatment for sepsis.

Summary for Lay Audience

Sepsis is a dysregulated immune response to infection and the leading cause of mortality globally, accounting for 11 million deaths in 2017. To date, no therapeutics are available to treat the underlying septic response. Previous research from our laboratory has shown that annexin A5 (Anx5) treatment increased survival by 40% in mice with endotoxemia, a model of sepsis. During sepsis, activated platelets (PLTs) release membrane fragments called extracellular vesicles with externalization of phosphatidylserine to which annexin A5 binds with a high affinity. We hypothesized that annexin A5 will block the pro-inflammatory response induced by activated PLTs and extracellular vesicles in vascular endothelial cells (ECs) under septic conditions. We showed that treatment with annexin A5 lowered expression of inflammatory cytokines and adhesion molecules induced by lipopolysaccharide (LPS)-activated PLTs or extracellular vesicles in ECs. Furthermore, annexin A5 treatment improved EC structural integrity and reduced monocyte adhesion to ECs in septic conditions. Our study shows that annexin A5 inhibits EC inflammation in septic conditions, suggesting its potential as a treatment for sepsis. Severe COVID-19 patients develop sepsis. A phase 2 clinical trial on the effects of annexin A5 in critically ill COVID-19 patients with sepsis is currently underway at London Health Sciences Centre.

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

Available for download on Friday, December 01, 2023

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