Blast-Associated Shock Waves Result in Increased Brain Vascular Leakage and Elevated ROS Levels in a Rat Model of Traumatic Brain Injury

Abstract

Blast-associated shock wave-induced traumatic brain injury (bTBI) remains a persistent risk for armed forces worldwide, yet its detailed pathophysiology remains to be fully investigated. In this study, we have designed and characterized a laboratory-scale shock tube to develop a rodent model of bTBI. Our blast tube, driven by a mixture of oxygen and acetylene, effectively generates blast overpressures of 20–130 psi, with pressure-time profiles similar to those of free-field blast waves. We tested our shock tube for brain injury response to various blast wave conditions in rats. The results show that blast waves cause diffuse vascular brain damage, as determined using a sensitive optical imaging method based on the fluorescence signal of Evans Blue dye extravasation developed in our laboratory. Vascular leakage increased with increasing blast overpressures and mapping of the brain slices for optical signal intensity indicated nonhomogeneous damage to the cerebral vasculature. We confirmed vascular leakage due to disruption in the blood-brain barrier (BBB) integrity following blast exposure. Reactive oxygen species (ROS) levels in the brain also increased with increasing blast pressures and with time post-blast wave exposure. Immunohistochemical analysis of the brain sections analyzed at different time points post blast exposure demonstrated astrocytosis and cell apoptosis, confirming sustained neuronal injury response. The main advantages of our shock-tube design are minimal jet effect and no requirement for specialized equipment or facilities, and effectively generate blast-associated shock waves that are relevant to battle-field conditions. Overall data suggest that increased oxidative stress and BBB disruption could be the crucial factors in the propagation and spread of neuronal degeneration following blast injury. Further studies are required to determine the interplay between increased ROS activity and BBB disruption to develop effective therapeutic strategies that can prevent the resulting cascade of neurodegeneration.

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

“…In other rat models, blast-induced BBB leakage appeared preferentially at higher blast pressures (>110-kPa), as it was shown that extensive leakage occurred in all brain regions but preferentially in the thalamus, striatum, hippocampus, and occipital cortex [25,29]. However, limited leakage, mainly through the chorionic plexus, was observed after exposure to 72-kPa blasts [25,29,49]. Kawoos et al [29] also showed that there is a qualitative relationship between BBB leakage and increased intracerebral pressure (ICP), through which the ICP levels and sustainability depend also on blast intensity and the number of blast exposures.…”

“…Acutely, after 72 h, animals exposed to 74.5-kPa blasts present pathological alterations that mainly included blood leakage from the choroid plexus into the lateral ventricles, focal non-hemorrhagic tissue tears, and vascular alterations [17,49]. In other rat models, blast-induced BBB leakage appeared preferentially at higher blast pressures (>110-kPa), as it was shown that extensive leakage occurred in all brain regions but preferentially in the thalamus, striatum, hippocampus, and occipital cortex [25,29]. However, limited leakage, mainly through the chorionic plexus, was observed after exposure to 72-kPa blasts [25,29,49].…”

“…Kawoos et al [29] also showed that there is a qualitative relationship between BBB leakage and increased intracerebral pressure (ICP), through which the ICP levels and sustainability depend also on blast intensity and the number of blast exposures. As blast induces an early vasodilation (as evidenced by enlarged blood vessel diameters [25]), the intravascular forces exercised by the pressurized circulating blood could damage the vascular Fig. 4 Selected cytokines in the brains of control and blast-exposed animals (6 weeks post-blast exposure).…”

“…Error bars indicate the standard error of the mean (SEM). Statistical differences indicated represent unpaired t-tests smooth muscle and endothelial layers [2,17,19,20,25,29,49,56]. Through buckling, it could induce vascular tortuosity [21] and through subsequent axial stretch [15], generate vascular strictures [17,49].…”

“…Through buckling, it could induce vascular tortuosity [21] and through subsequent axial stretch [15], generate vascular strictures [17,49]. In small vessels, endothelial damage can also lead to a breakdown of the BBB and blood leakage [25,29]. In large vessels, endothelial damage could trigger chronic vascular disease through vascular remodeling by induction of neointima formation, neointima thickening, restenosis, aneurysm formation, plaque deposition, vascular occlusion, thromboembolism, and vascular rupture.…”