Date of Award

2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Psychology

Abstract

Every 16 seconds in the United States, a person suffers a traumatic brain injury (TBI). The major problems in TBI patients are increased intracranial pressure (ICP), and diffuse global ischemia, which leads to cerebral hypoxia. Cerebral ischemia occurs in 65% of patients due to microvascular spasms and brain swelling. Subsequently, cerebral ischemia is exacerbated by the inflammatory processes initiated by microglia. Although therapeutic ICP control has resulted in mortality reduction, cerebral ischemia is still the major contributor to poor neurological outcome. To address this problem, an oxygen-guided therapy was introduced and has resulted in a reduction of both mortality and morbidity in acute TBI. But there are concerns that an increase in oxygen tension could lead to secondary brain injury mediated by microglia. This study examines the effect of various oxygen tensions on the activity of N9 microglia in an in vitro simulation of cerebral hypoxia. Cells were cultured at oxygen conditions that were commensurate with oxygen therapy in a clinical setting. Cell response was quantified by measuring the cellular release of the cytokines IL-1β, IL-6, and TNF-α and the release of nitric oxide (NO). Our results showed that an increase in oxygen tension abrogated in a dose-dependent manner the production of IL-1β and concomitantly increased the production of IL-6 and NO. TNF-α production was not affected by oxygen levels. Our results show that hypoxia alters the release of IL-1β, IL-6 and NO, and hence, contribute to a better understanding of the inflammatory mechanisms involved in the clinically used oxygen-guided therapy for patients with traumatic brain injury.

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