Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.702251
Title: Investigating the cerebral/pulmonary axis following traumatic brain injury in a preclinical model
Author: Humphries, Duncan Charles
ISNI:       0000 0004 6056 9880
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2015
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Abstract:
Traumatic Brain Injury (TBI) accounts for 1,000,000 hospital admissions in the European Union every year and is the leading cause of death in individuals under 45 years of age in both Europe and the United States. This thesis examines the consequences to both the brain and lung following TBI using the lateral fluid percussion injury (FPI) in an in-vivo murine model. In the murine FPI model, alongside cerebral inflammation (associated with neuronal damage and the infiltration of inflammatory cells), there is significant neutrophil accumulation within the pulmonary interstitium 6 and 24 hours after TBI. This was associated with pulmonary haemorrhage and increased vascular permeability. In an attempt to reduce pulmonary injury, 17-DMAG, an HSP90 inhibitor, was applied but proved to be nonprotective. Since patients with TBI show increased susceptibility to bacterial infection, microaspiration and ventilator-induced lung injury, a double-hit model was established whereby mice first received the head injury and then received a lung injury. This demonstrated worse lung injury following intra-tracheal administration of hydrochloric acid after TBI. Depleting neutrophils with an anti-LY-6G depleting antibody improved outcome in this model, indicating increased susceptibility to damage was neutrophil dependent. To test whether neutrophil accumulation within the pulmonary interstitium was specifically related to brain injury, lung tissue following other distant organ injury such as renal ischemia-reperfusion injury (IRI) and renal transplantation were assessed. Significant pulmonary interstitial neutrophil accumulation was seen following both models and was associated with significant pulmonary haemorrhage. Inducing HSP70 activity with an HSP90 inhibitor was shown to be protective by reducing the degree of pulmonary haemorrhage in these models. In an attempt to identify the mechanisms behind neutrophil accumulation in TBI, renal IRI and renal transplantation, ICAM-1 (CD54), a marker of the reverse transmigration of neutrophils was investigated. No differences in ICAM-1 expression were seen following TBI, indicating that another mechanism must be responsible. This mechanism is the focus of on going work within the laboratory. Hypoxia is believed to contribute towards the development of secondary brain injury however little is known regarding its direct contribution. Working alongside chemists at the University of Edinburgh, a number of novel fluorescent hypoxia probes were designed and tested, but none proved to be able to detect hypoxia in-vitro. In conclusion, this thesis has demonstrated that following mild TBI, the lungs are “primed” with a massive interstitial neutrophil influx and that a subsequent micro aspiration of acid induces exaggerated lung injury. The mechanism by which this occurs is the focus of on-going investigation. Pulmonary sequestration of neutrophils is also a predominant feature of other distant organ injuries.
Supervisor: Dhaliwal, Kanwaldeep ; Bradley, Mark ; Haslett, Christopher Sponsor: Medical Research Council (MRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.702251  DOI: Not available
Keywords: traumatic brain injury ; neutrophil ; acute brain injury ; acid microaspiration
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