Eye-Directed Overpressure Airwave-Induced Trauma Causes Lasting Damage to the Anterior and Posterior Globe: A Model for Testing Cell-Based Therapies

Abstract

Purpose: Characterization of the response of the Balb/c mouse to an eye-directed overpressure airwave, with the hypothesis that this mouse strain and model is useful for testing potential therapeutics for the treatment of traumatic eye injury. Methods: The left eyes of adult Balb/c mice were exposed to an eye-directed overpressure airwave. Intraocular pressure (IOP) was measured and eyes were inspected for gross pathology changes. Optical coherence tomography and histology were used to examine the structural integrity of the retina and optic nerve. Immunohistochemistry, in vivo molecular fluorophores, and a multiplex enzyme-linked immunosorbent assay were utilized to identify changes in cell death, neuroinflammation, and oxidative stress. Results: This model induced a transient increase in IOP, corneal injuries, infrequent large retinal detachments, retinal pigment epithelium (RPE) vacuolization, glial reactivity, and retinal cell death. Both the corneal damage and RPE vacuolization persisted with time. Optic nerve degeneration occurred as early as 7 days postinjury and persisted out to 60 days. Retinal cell death, increased levels of reactive oxygen species, and neuroinflammation were detected at 7 days postinjury. Conclusions: The injury profile of the Balb/c mouse is consistent with commonly observed pathologies in blastexposed patients. The damage is throughout the eye and persistent, making this mouse model useful for testing cell-based therapies.

Visual system pathology in humans and animal models of blast injury

“…A key requirement of blast models is the documentation of peak overpressures and their duration to ensure that the experimental design produces blast exposures comparable to what soldiers and civilians experience on the battlefield (Courtney & Courtney, ; Goldstein, McKee, & Stanton, ). Free‐field explosions (Hines‐Beard et al, ; Kuehn et al, ), shock tubes (DeMar et al, ; Petras et al, ), blast tubes (Elder, Stone, & Ahlers, ), and custom fabricated devices such as a modified nail gun (Kuehn et al, ) and a modified paint ball gun (Bricker‐Anthony, Hines‐Beard, & Rex, ; Bricker‐Anthony & Rex, ; Hines‐Beard et al, ; Guley et al, ; Heldt et al, ; Reiner et al, ) have been used to simulate primary blast injury. Advantages of the aforementioned custom fabricated models are low cost assembly, ease of use and the ability to isolate specific parameters of interest due to control of blast directed injury to the whole head (brain and eyes), specific regions of the cranium (brain only), and orbit (eye only).…”

“…Visual deficits, first detected as pathological changes in the central motor circuits controlling eye movement (Brahm et al, ; Greenwald, Kapoor, & Singh, ), are now known to include damage to the retina, leading several groups to focus on retinal pathology in animal models of blast injury (Bricker‐Anthony & Rex, ; Bricker‐Anthony et al, ; DeMar et al, ; Dutca et al, ; Greenwald et al, ; Mohan et al, ). Overall retinal ganglion cells (RGCs) and optic nerves are most vulnerable to injury (Choi et al, ; Dutca et al, ; Koliatsos et al, ; Mohan et al, ; Wang et al, ), although there are indications that photoreceptors and cells within the inner nuclear layer may incur delayed onset damage (Bricker‐Anthony & Rex, ; Dutca et al, ).…”

Modulation of post-traumatic immune response using anti-IL-1 therapy for improved visual outcomes: Anti-IL-1 improves post-traumatic visual outcomes

“…Although bTBI patients report a wide range of visual disturbances, little is known about the molecular mechanisms driving visual dysfunction. Murine bTBI models display many of the long-term visual deficits observed in patients, particularly retinal ganglion cell (RGC) dysfunction and subsequent cell death (Mohan, Kecova et al 2013, Dutca, Stasheff et al 2014, Bricker-Anthony, Hines-Beard et al 2016, Yin, Voorhees et al 2016, Evans, Newell et al 2018.…”

Erythropoietin either Prevents or Exacerbates Retinal Damage from Eye Trauma Depending on Treatment Timing

“…In contrast, focal oxidative stress, glial reactivity, cell death, and retinal detachments were present after an eye-directed air blast in both the Balb/c and DBA/2J mouse strains. 8, 11 In the DBA/2J mouse, cell death is greatest at 3 and 28-days post-blast, with very little cell death detected at 7-days post-blast. 8 Even at 3-days post-blast only about 10% of the retina contains TUNEL-positive cells.…”

“…In the Balb/c mouse, cell death is greatest at 7-days post-blast with an average of 50% of the retina containing TUNEL-positive cells. 11 Less of the retina is affected at 3 and 28-days post-blast. The effect of blast is most striking in the DBA/2J mouse, which has a high neuroinflammatory state.…”