Table 1.
Vascular and inflammatory changes in the nervous system following whole-body blast exposure in animal models.
| Species | Blast exposure | Vascular effects | Inflammatory effects | Reference |
|---|---|---|---|---|
| Rat | 110 kg TNT, exposed in a simulated bunker | Increased macrophages/microglia in pineal gland based on OX-42, OX-18, OX-6, and ED1 staining, increases at 7, 14, and 21 days after blast returning to normal by 28 days, most in perivascular locations | (38) | |
| Pig | Howitzer (9 and 30 kPa, peak overpressure, durations: 2.4 to 5.1 ms), bazooka (41 kPa, 1.9 ms), and automatic rifle (21–23 kPa, 0.7–1.3 ms) in open field or an enclosure | 3 and 7 days after three blast exposures, small parenchymal and subarachnoid hemorrhages predominately in occipital lobe, cerebellum, and medulla oblongata in animals exposed to bazooka, 30 kPa Howitzer, and automatic rifle in an open field, hemorrhages not observed in animals exposed to 9 kPa Howitzer or automatic rifle in enclosure | (39) | |
| Pig | Shock tube, live explosives in Humvee surrogate or building enclosure | Angiographic vasospasm immediately post-exposure in blast tube | Increased numbers of GFAP positive astrocytes | (40, 41) |
| Rat | Shock tube, 120 kPa | Transient increase in BBB permeability as judged by IgG immunostaining in superficial layers of cortex at 3 and 24 h post-exposure returning to normal 3 days after exposure | 4-hydroxynonenal (4-HNE) and 3-nitrotyrosine (3-NT) increased at 3 h after exposure, returned to control levels at 24 h post-exposure, 5 and 10 days post-exposure increased microglial binding of 3H-PK11195 in contralateral and ipsilateral dentate gyrus and at 10 days in the contralateral ventral hippocampus and substantia nigra, microglial morphology characteristic of activated microglia in hippocampus and substantia nigra by CD11b/c immunostaining | (42) |
| Mouse | Shock tube, 13.9, 20.6, and 25 psi single blast overpressure (BOP1) or three repeated blast exposures (BOP3) at 20.6 psi with 1 and 30 min intervals between successive exposures | Frequent subdural hemorrhages with BOP3 | Reactive oxygen species in cortex increased after BOP1 and BOP3 | (37) |
| Rat | Shock tube, 20.6 psi whole-body exposure combined with 1 week stress (predator scent exposure combined with unpredictable stress) | 2 months after blast/stress exposure, vascular endothelial cell growth factor (VEGF) elevated in hippocampus and prefrontal cortex | 2 months after blast/stress exposure, increased GFAP and Iba-1 immunoreactivity in hippocampus and prefrontal cortex | (43) |
| Rat | Open-field exposure to 120 kg TNT at 48.9 kPa (7.1 psi, positive pressure, duration 14.5 ms) or 77.3 kPa (11.3 psi, 18.2 ms) | Narrowed vasculature in cerebral cortex at 1 and 4 days after blast | Iba-1 immunostaining for macrophages or microglia not different from control | (44) |
| Mouse | Open-field explosives, 4 and 7 m distance from blast (5.5 and 2.5 psi) | Increased BBB permeability 1 month post-blast on contrast enhanced T1-weighted MRI images at 5.5 psi but not 2.5 psi exposure, no change in BBB permeability 7 days post-exposure | Upregulation of manganese superoxide dismutase 2 in neurons and CXC-motif chemokine receptor 3 around blood vessels in fiber tracts at 1 month post-exposure | (45) |
| Mouse | Modular, multi-chamber shock tube capable of reproducing complex shock wave signatures, 68, 76, or 105 kPa exposures with durations 4–5 ms | Animals subjected to mild (68 kPa) or moderate (76 kPa) showed elevated mRNA for GFAP, myeloid related protein 8 (MCP-8), chemokine CC ligand-2 (CCL2/MCP1), and ED-1 in hippocampus and brainstem from 1–30 days post-exposure | (46) | |
| Rat | Shock tube, 36.6 kPa (duration 4.1 ms), 74.5 kPa (4.8 ms) or 116.7 kPa (6.8 ms) | 116.7 kPa overt threshold for pathology with 30% of rats having subdural hemorrhage and cortical contusions, all animals exposed to 116.7 kPa had pulmonary hemorrhages | (35) | |
| Mouse | Shock tube, 77 kPa, positive pressure duration 4.8 ms | Microvasculopathy 2 weeks after exposure to blast with dysmorphic capillaries, thickened basal lamina, and swollen astrocytic end feet processes in the absence of macroscopic tissue damage or hemorrhage, perivascular tau accumulation | Activated microglia throughout brain, especially cerebellum 2 weeks after blast exposure based on Ricinus communis agglutinin immunostaining | (23) |
| Rat | Shock tube, 90–193 kPa, duration ~10 ms | Decreased cerebral blood flow in the internal cerebral vein by susceptibility-weighted imaging (SWI) 24 and 48 h at exposures of 117, 159, or 193 kPa or higher, reduced cerebral blood flow by continuous arterial spin-labeling (ASL) in hippocampus, auditory cortex, medial dorsal cortex, and thalamus | (47) | |
| Rat | Shock tube, 230–380 kPa, subjected to on axis composite blast (blast wave plus pressure jet, duration 3–5 ms) or off axis (blast wave only, duration 50–100 μs) exposures | Gliosis in hippocampus as judged by GFAP immunostaining 1 and 7 days after both primary and composite blast | (48) | |
| Rat | Shock tube, 120 kPa, positive pressure duration ~3 ms | Deposition of C3/C5b-9 in superficial layers of neocortex mostly around blood vessels at 3 and 48 h, elevated C3 by Western blot in neocortex at 3 and 48 h, CD45+leukocytes in neocortex at 3 and 48 h, increased TNF-α in neocortex at 3 h but not 48 h by Western blotting and immunostaining, increased aquaporin-4 expression in superficial layers of neocortex at 3 h, C3/C5b-9 deposition around neurons in the hippocampus | (49) | |
| Monkey | 120 kg TNT at 19 or 24 m (80 kPa or 200 kPa with ~10 ms duration) | By EM capillaries showed collapsed lumens, hypertrophic astrocyte end-feet, and vacuolated or electron dense endothelial cell cytoplasm, fluorescent perithelial cells (Mato cells) appeared to increase in number | Astrocytic hypertrophy | (50) |
| Rat | Shock tube, one or two 123 kPa exposures | 6–24 h after exposure reduction of the BBB tight-junction proteins occludin, claudin-5, and zonula occludens 1 in brain microvessels with loss of the pericyte marker PDGF-β, activation of caspase-3 and cell apoptosis mostly around perivascular regions, increased permeability of Evans blue and sodium-fluorescein low molecular-weight tracers | 6–24 h after exposure infiltration of immune cells across the BBB, induction of the free radical-generating enzymes NADPH oxidase 1 and inducible nitric oxide synthase along with evidence of oxidative and nitrosative damage (4-HNE/3-NT), activation of matrix metalloproteinases and fluid channel aquaporin-4 | (51) |
| Rat | Shock tube, single or multiple (three) 74.5 kPa (duration 4.8 ms) | Frequent intraventricular hemorrhages after 24 h, no generalized histopathology in animals between 4 and 10 months after exposure but focal lesions resembling rips or tears found in many brains that frequently appeared to follow the lines of penetrating cortical vessels often disrupting cortical organization, microhemorrhages found within some but not most acute lesions | Microglial activation around focal cortical lesions | (52) |
| Mouse | 20.6 psi, three with 1–30 min intervals between exposures | Histological evidence of constriction of blood vessels at 4 h after exposure | Altered RNA levels of multiple inflammation related genes including TNF family, interleukins and interleukin receptors, increased myeloperoxidase activity in cerebellum | (53, 54) |
| Rat | Shock tube, 129 kPa (duration 2.5 ms) | Increased reactive oxygen species in brain, upregulation of mRNA and protein expression of pro-inflammatory mediators, IFN-γ and MCP-1, microglial activation (increased Iba-1 immunostaining) at 2 weeks but not at 4, 24, or 48 h | (55) | |
| Rat | Shock tube, single blast at 130, 190, 230, 250, and 290 kPa (impulses 184–452 Pa*s) | Diffuse BBB breakdown indicated by immunoglobulin G (IgG) immunostaining at 190 kPa and above sacrificed 24 h post-exposure | (56) | |
| Rat | Shock tube, single or multiple (3) 74.5 kPa (duration 4.8 ms) | Microvascular pathology present at 24 h after injury within an otherwise normal brain parenchyma by electron microscopy, chronic changes in the microvasculature and altered collagen IV and laminin immunostaining of brain microvessels many months after blast exposure | (57) | |
| Rat | Shock tube, single 120 kPa exposure | Elevated RANTES in cortex at 24 h after blast | (58) | |
| Goat | Exposure to TNT in column-like buildings at 2–8 m from detonation, blast wave composed of two peaks from incident and reflected wave varying from 555/913 (peak/reflected) kPa at 2 m to 45/71 kPa at 8 m (durations 0.6–2.7 ms) | 4 h after exposure at 2 m diffuse congestion of the vasculature on the surface of the brain with extensive subarachnoid and parenchymal hemorrhage visible grossly and microscopically, hemorrhagic component less pronounced but still present at 8 m exposures | (33) | |
| Rat | Shock tube, 117 kPa, duration 7.5 ms | Increased number of GFAP-positive astrocytes in prefrontal cortex at 168 h after injury, no change in Iba-1-labeled microglia | (59) | |
| Rat | Shock tube, 69, 97, and 165 kPa (10, 14, or 24 psi), positive pressure duration 2.5 ms | 7 days post-injury activation of microglia in hippocampus of 69 kPa group, increased GFAP-positive astrocytes in hippocampus of 97 and 165 kPa groups | (60, 61) |