Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology

Supervisor

Dr. Douglas Fraser

Abstract

Sepsis-associated encephalopathy (SAE) is an independent predictor of mortality in severe sepsis patients. Mechanisms of SAE are poorly characterized. Pro-inflammatory mediators are up-regulated in blood plasma of severe sepsis patients and may lead to activation/dysfunction of cerebrovascular endothelial cells (CMEC) of the blood-brain barrier (BBB) – potentially contributing to brain dysfunction. The objective of the present study was to determine the effects/mechanisms of both human severe sepsis blood plasma (hSSP; 20% v/v) and a mixture of 8 cytokines/chemokines that mimicked physiological concentrations of cytokines/chemokines in hSSP (cytomix; SSCM) on human-derived CMEC (hCMEC/D3) activation/dysfunction

in vitro. hSSP-stimulation up-regulated hCMEC/D3 pro-adhesive phenotype as evidenced by polymorphonuclear leukocyte (PMN; neutrophils) adhesion under conditions of flow. In contrast, up-regulation of the PMN pro-adhesive phenotype was observed following stimulation with the severe sepsis cytomix. These findings suggest that PMN-endothelial interactions may play a key role in dysfunction of cerebrovascular endothelium during severe sepsis.


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