Production and impaired regulation of neutrophil extracellular traps following severe thermal injury, implications for sepsis and multiple organ failure

Dinsdale, Robert Johnathon (2017). Production and impaired regulation of neutrophil extracellular traps following severe thermal injury, implications for sepsis and multiple organ failure. University of Birmingham. Ph.D.

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Abstract

Advancements in burn care have improved immediate outcome, however, the prevalence of sepsis and multiple organ failure (MOF) remain significant. Although well characterised the mechanisms responsible for the pathogenesis of MOF and increased propensity to infection are poorly understood. Neutrophil extracellular traps (NETs) provide protection against invading pathogens but also contribute to thrombosis.

Sepsis is required for NET generation following severe thermal injury. Quantification of circulating NET biomarkers shows good discriminatory power for diagnosis of sepsis. Interestingly, neutrophils isolated from 24 patients with severe thermal injuries, ≥ 15% total body surface area, had a significantly reduced ability to form NETs ex vivo, potentially mediated by phenotypical changes of neutrophils and inhibitory effects of formyl peptides.

This thesis identified a major biological mechanism driving MOF after severe thermal injury, namely the compromise to the actin scavenging system which leads to reduced DNAse activity and a build-up of circulating DNA. Preliminary analysis suggests that DNAse activity can be restored by prehospital use of fresh frozen plasma following major trauma. Thus, administration of blood products or manipulation of the actin scavenging system is a potential therapeutic target.

This thesis has identified a number of novel mechanisms responsible for the regulation of NETs following severe thermal injuries and their implications for sepsis and MOF.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):