Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology and Pharmacology

Supervisor

Dr. Douglas D. Fraser

Abstract

Diabetic Ketoacidosis (DKA) is associated with pediatric cerebrovascular-related complications. DKA-associated inflammation instigates leukocyte adherence to the brain microvascular endothelium. As adhered leukocytes release enzymes that compromise vascular integrity, we questioned a role for leukocyte-derived matrix metalloproteinases (MMPs) and azurophilic enzymes (elastase, proteinase-3, myeloperoxidase). Our aims were to measure leukocyte-derived enzymes in DKA plasma, determine associations with DKA severity and investigate their effect on the cerebrovascular endothelium.

Plasma was obtained from children with type-1 diabetes, either in acute DKA or insulin-controlled. DKA was associated with altered plasma levels of ↓MMP-2, ↑MMP-8, ↑MMP-9 and ↑TIMP-4, which are largely leukocyte in origin. DKA was also associated with elevated plasma leukocyte elastase, proteinase-3 and myeloperoxidase. MMP-8, MMP-9 and proteinase-3 were positively correlated with DKA severity. Azurophilic enzymes decreased ZO-1 and degraded β-catenin in cerebrovascular endothelium.

In summary, DKA is associated with dynamic regulation of leukocyte proteolytic enzymes that can impair blood brain barrier integrity.


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