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Axonopathy precedes cell death in ocular damage mediated by blast exposure.

ABSTRACT: Traumatic brain injuries (TBI) of varied types are common across all populations and can cause visual problems. For military personnel in combat settings, injuries from blast exposures (bTBI) are prevalent and arise from a myriad of different situations. To model these diverse conditions, we are one of several groups modeling bTBI using mice in varying ways. Here, we report a refined analysis of retinal ganglion cell (RGC) damage in male C57BL/6J mice exposed to a blast-wave in an enclosed chamber. Ganglion cell layer thickness, RGC density (BRN3A and RBPMS immunoreactivity), cellular density of ganglion cell layer (hematoxylin and eosin staining), and axon numbers (paraphenylenediamine staining) were quantified at timepoints ranging from 1 to 17-weeks. RNA sequencing was performed at 1-week and 5-weeks post-injury. Earliest indices of damage, evident by 1-week post-injury, are a loss of RGC marker expression, damage to RGC axons, and increase in glial markers expression. Blast exposure caused a loss of RGC somas and axons-with greatest loss occurring by 5-weeks post-injury. While indices of glial involvement are prominent early, they quickly subside as RGCs are lost. The finding that axonopathy precedes soma loss resembles pathology observed in mouse models of glaucoma, suggesting similar mechanisms.

SUBMITTER: Boehme NA

PROVIDER: S-EPMC8175471 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Axonopathy precedes cell death in ocular damage mediated by blast exposure.

Boehme Nickolas A NA Hedberg-Buenz Adam A Tatro Nicole N Bielecki Michael M Castonguay William C WC Scheetz Todd E TE Anderson Michael G MG Dutca Laura M LM

Scientific reports 20210603 1

Traumatic brain injuries (TBI) of varied types are common across all populations and can cause visual problems. For military personnel in combat settings, injuries from blast exposures (bTBI) are prevalent and arise from a myriad of different situations. To model these diverse conditions, we are one of several groups modeling bTBI using mice in varying ways. Here, we report a refined analysis of retinal ganglion cell (RGC) damage in male C57BL/6J mice exposed to a blast-wave in an enclosed chamb ...[more]

PMID: 34083587

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Project description:Background and objectiveBomb blast injuries exerts a shearing force on the air-tissue interfaces, causing devastating ocular injury from the blast wave. Improvised explosive devices (IEDs) are usually placed at different heights from the ground to induce more severe injury through ground blast reinforcement (GBR). However, there is still a lack of knowledge of the role of GBR and IED height from the ground on ocular biomechanics, and how they can affect the intraocular pressure (IOP) in the eye. This study aimed to estimate the IOP due to frontal IED explosion at different heights from the ground using a fluid-structure interaction model with and without GBR effects.MethodsA 2 kg IED was placed within 5 m of the victim at 5 different heights from the ground, including 0, 0.42, 0.85, 1.27, and 1.70 m. Two different blast formulations were used to simulate the IED explosion: (a) spherical airburst, with no amplification of the initial shock wave due to interaction with the ground-surface, and (b) hemispherical surface-burst, where the initial blast wave is immediately reflected and reinforced by the ground (GBR).ResultsResults revealed that the blast wave due to GBR reaches to the skull prior to the IED blast itself. The GBR also reached to the skull ∼ 0.6 ms earlier when the IED was on the ground compared to the height of 1.70 m. The highest and lowest IOPs of ∼ 17,000 and ∼ 15,000 mmHg were observed at the IED heights of 1.70 and 0 m from the ground considering GBR. However, when the role of the GBR is ignored, IOP of ∼ 9,000 mmHg was observed regardless of the IED height from the ground. The deformation in the apex of the cornea was higher when considering the GBR (∼ 0.75 cm) versus no GBR (∼ 0.65 cm). Considering GBR led to higher stresses and strains in the sclera.ConclusionsWhen the role of GBR was ignored, the results showed similar patterns and magnitudes of stresses and deformations in the skull and eye regardless of the height of the IED from the ground, which was not the case when GBR was considered. The findings of this study suggest the critical role of GBR in ocular blast simulations.

Project description:Visual deficits are a common concern among subjects with head trauma. Stem cell therapies have gained recent attention in treating visual deficits following head trauma. Previously, we have shown that adipose-derived stem cell (ASC) concentrated conditioned medium (ASC-CCM), when delivered via an intravitreal route, yielded a significant improvement in vision accompanied by a decrease in retinal neuroinflammation in a focal cranial blast model that indirectly injures the retina. The purpose of the current study is to extend our previous studies to a direct ocular blast injury model to further establish the preclinical efficacy of ASC-CCM. Adult C57BL/6J mice were subjected to repetitive ocular blast injury (rOBI) of 25 psi to the left eye, followed by intravitreal delivery of ASC-CCM (∼200 ng protein/2 μl) or saline within 2-3 h. Visual function and histological changes were measured 4 weeks after injury and treatment. In vitro, Müller cells were used to evaluate the antioxidant effect of ASC-CCM. Visual acuity, contrast sensitivity, and b-wave amplitudes in rOBI mice receiving saline were significantly decreased compared with age-matched sham blast mice. Immunohistological analyses demonstrated a significant increase in glial fibrillary acidic protein (a retinal injury marker) in Müller cell processes, DNA/RNA damage, and nitrotyrosine (indicative of oxidative stress) in the retina, while qPCR analysis revealed a >2-fold increase in pro-inflammatory cytokines (TNF-α, ICAM1, and Ccl2) in the retina, as well as markers for microglia/macrophage activation (IL-1β and CD86). Remarkably, rOBI mice that received ASC-CCM demonstrated a significant improvement in visual function compared to saline-treated rOBI mice, with visual acuity, contrast sensitivity, and b-wave amplitudes that were not different from those in sham mice. This improvement in visual function also was associated with a significant reduction in retinal GFAP, neuroinflammation markers, and oxidative stress compared to saline-treated rOBI mice. In vitro, Müller cells exposed to oxidative stress via increasing doses of hydrogen peroxide demonstrated decreased viability, increased GFAP mRNA expression, and reduced activity for the antioxidant catalase. On the other hand, oxidatively stressed Müller cells pre-incubated with ASC-CCM showed normalized GFAP, viability, and catalase activity. In conclusion, our study demonstrates that a single intravitreal injection of ASC-CCM in the rOBI can significantly rescue retinal injury and provide significant restoration of visual function. Our in vitro studies suggest that the antioxidant catalase may play a major role in the protective effects of ASC-CCM, uncovering yet another aspect of the multifaceted benefits of ASC secretome therapies in neurotrauma.

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Axonopathy precedes cell death in ocular damage mediated by blast exposure.

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Axonopathy precedes cell death in ocular damage mediated by blast exposure.

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