|dc.description.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.||en