The effect of polytrauma on TBI outcomes, and identifying novel treatment strategies
Polytrauma, an injury that involves at least two body regions, is prevalent worldwide and a major cause of morbidity and mortality. The combination of traumatic brain injury (TBI) plus extracranial injury (ECI) is a common form of polytrauma. TBI is a leading cause of death and disability, and there is no treatment known to improve long-term outcomes. The physiology of TBI is complex and may involve blood-brain barrier (BBB) disruption, oedema, apoptosis, neuroinflammation, and oxidative stress, all of which may contribute to brain damage and functional deficits post-TBI. Importantly, BBB damage facilitates the migration of peripheral factors into the brain which may impact TBI pathobiology. ECI can induce a systemic response in which immune cells are activated and secrete inflammatory mediators into the circulation, and these same mediators can modulate TBI pathophysiology. Therefore, ECI (i.e., polytrauma) may exacerbate TBI outcomes. We recently developed an internationally unique mouse model of polytrauma which has both TBI and tibial fracture to investigate this relationship . Mice given polytrauma have elevated neuroinflammation, oxidative stress, and brain damage, and worse behavioural deficits than mice given only a TBI. Our published findings demonstrate that the presence of an ECI worsens TBI outcomes, and provide novel insight into the possible mechanisms that may underlie these effects.
We now aim to:
- Aim 1: Assess the use of clinically translatable IL-1 receptor antagonist (IL-1ra) treatment to target inflammation and improve TBI outcomes in a novel polytrauma model.
- Aim 2: Assess the use of clinically translatable and pleiotropic thymosin β4 (Tβ4) treatment to improve TBI and fracture outcomes in our novel polytrauma model.
- Aim 3: Investigate pathophysiology and long-term outcomes in human polytrauma patients.
Trauma injuries are a serious medical problem, of which TBI is often a major component. No treatment is known to improve long-term TBI outcomes, which is in part due to our poor understanding of TBI physiology and how factors such as ECI can impact this process. Our multidisciplinary research team of international clinical and basic science leaders in trauma will utilize an innovative translational research approach to study the pathophysiology and treatment of TBI, fracture, and polytrauma. Of the utmost importance, the treatments in Aims 1 and 2 have clear translational pathways to clinical trials, and we are well-placed to pursue these, if Aim 3 finds that an ECI affects human TBI patients in a manner similar to our model.
- Rhys Brady, Research Assistant
- Mujun Sun, PhD Student
- Dr. Stuart McDonald, Department of Physiology, La Trobe University
- Professor Denes Agoston, Uniformed Services University of Health Sciences, USA
- McDonald SJ, Sun M, Agoston DV, Shultz SR. The effect of concomitant
peripheral injury on traumatic brain injury pathobiology and outcome. J
Neuroinflammation. 2016 Apr 26;13(1):90. doi: 10.1186/s12974-016-0555-1. Review.
PubMed PMID: 27117191; PubMed Central PMCID: PMC4847339 .
- Shultz SR, Sun M, Wright DK, Brady RD, Liu S, Beynon S, Schmidt SF, Kaye AH,
Hamilton JA, O'Brien TJ, Grills BL, McDonald SJ. Tibial fracture exacerbates
traumatic brain injury outcomes and neuroinflammation in a novel mouse model of
multitrauma. J Cereb Blood Flow Metab. 2015 Aug;35(8):1339-47. doi:
10.1038/jcbfm.2015.56. Epub 2015 Apr 8. PubMed PMID: 25853909; PubMed Central
- McDonald SJ, Sun M, Agoston DV, Shultz SR. The effect of concomitantperipheral injury on traumatic brain injury pathobiology and outcome. JNeuroinflammation. 2016 Apr 26;13(1):90. doi: 10.1186/s12974-016-0555-1. Review. PubMed PMID: 27117191; PubMed Central PMCID: PMC4847339
- Shultz SR, Sun M, Wright DK, Brady RD, Liu S, Beynon S, Schmidt SF, Kaye AH,Hamilton JA, O'Brien TJ, Grills BL, McDonald SJ. Tibial fracture exacerbatestraumatic brain injury outcomes and neuroinflammation in a novel mouse model ofmultitrauma. J Cereb Blood Flow Metab. 2015 Aug;35(8):1339-47. doi:10.1038/jcbfm.2015.56. Epub 2015 Apr 8. PubMed PMID: 25853909; PubMed CentralPMCID: PMC4528010.
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