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

Shushi Kabu,Michael Courtney,Dave Dudzinski,Marianne Petro,Amy Courtney,Desiree Stewart,Hayder Jaffer,Vinod Labhasetwar,Mária A Deli

doi:10.1371/journal.pone.0127971

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.

Highlights

The frequent use of improvised explosive devices makes blast injury a constant threat for military troops deployed in areas of conflict
The current system used for categorizing blast injuries is based on the nature of the initial mechanical insult, classifying the resulting injury into any of the four types of Blast-associated shock wave-induced traumatic brain injury (bTBI): primary, secondary, tertiary, or quaternary [3]
The pressure-time profiles of the shock waves generated by different driver section configurations were typical to the Friedlander waveform of free-field blast waves (Fig 2A)

Summary

Introduction

The frequent use of improvised explosive devices makes blast injury a constant threat for military troops deployed in areas of conflict. To progression over time and eventual outcome, the nature of bTBI is varied and heterogeneous, presenting itself in dissimilar physical characteristics and resultant neuronal consequences [3]. The current system used for categorizing blast injuries is based on the nature of the initial mechanical insult, classifying the resulting injury into any of the four types of bTBI: primary (caused by the direct effect of a blast wave), secondary (caused due to the physical contact of the victim with blast debris and fragments), tertiary (occurring when the victim is physically displaced by the blast wave and winds), or quaternary (resulting from chemical and thermal damage caused by the blast) [3]. The exact transduction pathway that causes bTBI remains unknown, probable mechanisms include a) direct passage of the blast wave via the skull, causing mechanical disruptions, acceleration and/or rotation of the head and b) indirect passage of the blast wave though the vascular system, resulting in propagation of localized high pressures (“overpressures”) and/or sudden disruptions to the blood flow [4,5]

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