Abstract
Traumatic brain injury (TBI) is a major health problem for over 3.17 million people in the US, attracting increasing public attentions. Understanding the underlying mechanism of TBI is urgent for better diagnosis and treatment. Here, we examined the hypothesis that cerebral hemorrhagic coagulation and subsequent immune cells infiltration causes the progressive mechanisms of brain injury in moderate fluid percussion injury model. This represents a subdural hematoma and hemorrhagic head injury. We found increased hemorrhagic lesions and infarct volume in the injured brain with increment of pressure. The extent of hemorrhage was also validated by the bio-distribution of fluorescent tracer in cerebrospinal fluid (CSF) pathway after the injury. Bio-distribution of tracer was specifically diminished at the site of hemorrhage resulting from coagulation, which blocked the interstitial and CSF movement of the tracer. Increased expression of coagulation factor XII and necrotic cell death in and around the impact site confirmed the reason for this blockade. Different biomarkers, including immune cells accumulation and neuronal death showed that blood-brain barrier disruption played an important role for induction of neuroinflammation and neurodegeneration around the impact site. Our results suggest that instant hemorrhagic injury resulting from rupturing the brain blood vessels intertwined with coagulation causes onsite perivascular inflammation and neurodegeneration. Understanding of this sequential event should be valuable for development of therapeutic treatment in TBI.
Underlying mechanisms in moderate/severe blunt TBI: hemorrhage following cerebrovascular disruption results in coagulation, thrombotic necrosis, and acute immune cell infiltration.
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Acknowledgements
We thank Dr. Eun Jung Lee, Dr. Namas Chandra and Daniel Younger for help of imaging and section scanning. This work was supported by grant 1R21AA022734-01A1 (to JH) from National Institutes of Health.
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XM carried out the studies, performed the data acquisition and writing in manuscript preparation. YC assisted XM in surgery and data analysis. RG assisted in animal care and surgery. JH supervised the development of work, gave critical revisions and edited the manuscript. All authors read and approved the final manuscript.
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Ma, X., Cheng, Y., Garcia, R. et al. Hemorrhage Associated Mechanisms of Neuroinflammation in Experimental Traumatic Brain Injury. J Neuroimmune Pharmacol 15, 181–195 (2020). https://doi.org/10.1007/s11481-019-09882-x
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DOI: https://doi.org/10.1007/s11481-019-09882-x