title: 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.
authors.affiliation: Lerner Research Institute, Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Shushi
authors.initials: S
authors.lastname: Kabu
authors.affiliation: Lerner Research Institute, Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Hayder
authors.initials: H
authors.lastname: Jaffer
authors.affiliation: Lerner Research Institute, Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Marianne
authors.initials: M
authors.lastname: Petro
authors.affiliation: Lerner Research Institute, Medical Device Solutions, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Dave
authors.initials: D
authors.lastname: Dudzinski
authors.affiliation: Lerner Research Institute, Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Desiree
authors.initials: D
authors.lastname: Stewart
authors.affiliation: BTG Research, Colorado Springs, Colorado, United States of America.
authors.forename: Amy
authors.initials: A
authors.lastname: Courtney
authors.affiliation: BTG Research, Colorado Springs, Colorado, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Courtney
authors.affiliation: Lerner Research Institute, Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Vinod
authors.initials: V
authors.lastname: Labhasetwar
mesh_terms: D000818:Animals; D001753:Blast Injuries / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D001808:Blood Vessels / Q000473:pathology; D001812:Blood-Brain Barrier / Q000503:physiopathology; D001921:Brain / Q000098:blood supply / Q000503:physiopathology*; D001929:Brain Edema / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D004867:Equipment Design; D008297:Male; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species