Lack of chronic neuroinflammation in the absence of focal hemorrhage in a rat model of low-energy blast-induced TBI

Abstract

Blast-related traumatic brain injury (TBI) has been a common cause of injury in the recent conflicts in Iraq and Afghanistan. Blast waves can damage blood vessels, neurons, and glial cells within the brain. Acutely, depending on the blast energy, blast wave duration, and number of exposures, blast waves disrupt the blood-brain barrier, triggering microglial activation and neuroinflammation. Recently, there has been much interest in the role that ongoing neuroinflammation may play in the chronic effects of TBI. Here, we investigated whether chronic neuroinflammation is present in a rat model of repetitive low-energy blast exposure. Six weeks after three 74.5-kPa blast exposures, and in the absence of hemorrhage, no significant alteration in the level of microglia activation was found. At 6 weeks after blast exposure, plasma levels of fractalkine, interleukin-1β, lipopolysaccharide-inducible CXC chemokine, macrophage inflammatory protein 1α, and vascular endothelial growth factor were decreased. However, no differences in cytokine levels were detected between blast-exposed and control rats at 40 weeks. In brain, isolated changes were seen in levels of selected cytokines at 6 weeks following blast exposure, but none of these changes was found in both hemispheres or at 40 weeks after blast exposure. Notably, one animal with a focal hemorrhagic tear showed chronic microglial activation around the lesion 16 weeks post-blast exposure. These findings suggest that focal hemorrhage can trigger chronic focal neuroinflammation following blast-induced TBI, but that in the absence of hemorrhage, chronic neuroinflammation is not a general feature of low-level blast injury.

Low-level blast exposure disrupts gliovascular and neurovascular connections and induces a chronic vascular pathology in rat brain

“…Because multiple blast exposures have been common among veterans returning from Iraq and Afghanistan [28], for most studies we used a design in which rats received three 74.5-kPa exposures delivered one exposure per day on 3 consecutive days. In multiple studies using this design we confirmed the lack of neuronal pathology at the light and EM levels as well as the absence of any reactive astrocytosis or general inflammatory reaction [2, 22, 26, 31–33] despite the fact that these animals develop chronic PTSD-related behavioral traits [26, 64–67]. Thus based on our experience presented in a number of published studies we believe that these blast pressures mimic a low-level blast exposure equivalent to a human mTBI or subclinical blast exposure.…”

“…We have been studying a rat model developed to mimic blast exposures that would be associated with human mTBI or a subclinical exposure, an exposure that we refer to as “low-level” [29]. In multiple studies the lack of generalized neuronal pathology at the light and EM levels has been confirmed as well as the absence of any generalized reactive astrocytosis or inflammatory reaction [2, 22, 26, 31–33]. Because multiple blast exposures have been common among veterans returning from Iraq and Afghanistan [28], for most studies including the present we used a design in which rats received three exposures delivered one per day on 3 consecutive days.…”

“…The peak pressure at the end of the expansion chamber was determined by piezoresistive gauges specifically designed for pressure-time (impulse) measurements (Model 102 M152, PCB, Piezotronics, Inc., Depew, NY, USA). This apparatus has been used in multiple prior studies to deliver blast overpressure injury to rats [2, 15–17, 22, 26, 31–33, 38, 64–66].…”

Repetitive head injury in adolescent mice: A role for vascular inflammation

“…Similar to our results, repetitive low-level blast TBI in adult rats did not induce gliosis and overt histopathology in the chronic stages. 44 Indeed, the current study shows that repetitive TBI in adolescent mice can lead to long-term, progressive neurological dysfunction in the absence of significant histopathology. These findings have important implications for adolescents who play contact sports or are otherwise at risk of repetitive head injury, inasmuch as mechanisms other than or in addition to those associated with CTE may be relevant to development of impaired neurological function later in life.…”

Potential Health and Performance Effects of High-Level and Low-Level Blast: A Scoping Review of Two Decades of Research

“…Animal studies used predominately rats ( 45 , 48 – 51 , 53 – 57 , 59 – 62 , 65 , 66 ). Sample sizes in studies using rats ranged from 10 to 180, with 75% of studies including fewer than 100 subjects.…”