Abstract
Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. Our understanding of its pathobiology has substantially increased. Following TBI, the following occur, edema formation, brain swelling, increased intracranial pressure, changes in cerebral blood flow, hypoxia, neuroinflammation, oxidative stress, excitotoxicity, and apoptosis. Experimental animal models have been developed. However, the difficulty in mimicking human TBI explains why few neuroprotective strategies, drawn up on the basis of experimental studies, have translated into improved therapeutic strategies for TBI patients. In this study, we retrospectively examined brain samples in 145 cases of death after different survival times following TBI, to investigate aquaporin-4 (AQP4) expression and correlation with hypoxia, and neuroinflammation in human TBI. Antibodies anti-glial fibrillary acid protein (GFAP), aquaporin-4 (AQP4), hypoxia induced factor-1α (HIF-1α), macrophage/phagocytic activation (CD68), ionized calcium-binding adapter molecule-1 (IBA-1), and neutrophils (CD15) were used. AQP4 showed a significant, progressive increase between the control group and groups 2 (one-day survival) and 3 (three-day survival). There were further increases in AQP4 immunopositivity in groups 4 (seven-day survival), 5 (14-dayssurvival), and 6 (30-day survival), suggesting an upregulation of AQP4 at 7 to 30 days compared to group 1. GFAP showed its highest expression in non-acute cases at the astrocytic level compared with the acute TBI group. Data emerging from the HIF-1α reaction showed a progressive, significant increase. Immunohistochemistry with IBA-1 revealed activated microglia starting three days after trauma and progressively increasing in the next 15 to 20 days after the initial trauma. CD68 expression demonstrated basal macrophage and phagocytic activation mostly around blood vessels. Starting from one to three days of survival after TBI, an increase in the number of CD68 cells was progressively observed; at 15 and 30 days of survival, CD68 showed the most abundant immunopositivity inside or around the areas of necrosis. These findings need to be developed further to gain insight into the mechanisms through which brain AQP4 is upregulated. This could be of the utmost clinicopathological importance.
Highlights
Current estimates from the World Health Organization (WHO) suggest that traumatic brain injury (TBI) will be the third leading cause of death and disability by the year 2020 [1,2]
The negative effects of brain trauma are determined by the entity of the primary injury resulting from a direct or indirect biomechanical force on the brain matter. Secondary events, such as edema formation, brain swelling, increased intracranial pressure, changes in cerebral blood flow associated with hypoxia, neuroinflammation, oxidative stress, excitotoxicity, and apoptosis [5,6], may occur with some delay, and may greatly affect the patient’s outcome [7]
We investigated the presence of this single nucleotide polymorphism (SNP) on the AQP4 gene in our study population, excluding all samples with this genetic variant
Summary
Current estimates from the World Health Organization (WHO) suggest that traumatic brain injury (TBI) will be the third leading cause of death and disability by the year 2020 [1,2]. It is still difficult to calculate an average incidence and mortality rate since there is considerable variation in case definitions, including criteria and methods used in the studies [4]. The negative effects of brain trauma are determined by the entity of the primary injury resulting from a direct or indirect biomechanical force on the brain matter. Secondary events, such as edema formation, brain swelling, increased intracranial pressure, changes in cerebral blood flow associated with hypoxia, neuroinflammation, oxidative stress, excitotoxicity, and apoptosis [5,6], may occur with some delay, and may greatly affect the patient’s outcome [7]. Regardless of the cause of brain injury, brain edema almost always occurs and is heavily involved in the pathophysiology of brain damage following traumatic injury, being a central part of the vicious cycle of injury in TBI and the major determinant of patient prognosis [7,8,9,10,11,12]
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