Abstract
Purpose :
The purpose of this work is to generate a human-relevant model of blast induced traumatic optic neuropathy (TON) in tree shrew (Tupaia belangeri). Unlike mouse and rat, tree shrews have greater similarity to human genetic and epigenetic variations, visual system features, and genomic and transcriptomic expression levels, which we hypothesize will improve the clinical translation of regenerative therapies.
Methods :
Ocular trauma was induced by exposing one eye and/or surrounding tissue (e.g., brow ridge, side of head posterior to eye) of an anesthetized tree shrew to repeated bursts of overpressure air (15-55psi). Sham tree shrews were anesthetized and placed into the air blast chamber but were not exposed to the overpressure air. At baseline and over time post-injury, electroretinograms (ERGs), visual evoked potentials (VEPs), and optical coherence tomography (OCT) were recorded. At study end point, eye and ON tissue were collected for histological and immunohistochemical analysis.
Results :
In mouse, blast-induced TON occurs by 7 days following 3 blasts of 15psi. In tree shrew, ON injury was not seen following conseuctive eye-directed blasts of up to 15psi, despite increasing the number of blasts to 10. Here, ON injury was not seen in tree shrew until 2 weeks following 20 blasts of 20psi, resulting in an initial increase in degenerative axon profiles and prolonged reductions in total axon counts out to 8 weeks. In this cohort, decreased retinal function was observed at 4 weeks and partially recovered by 8 weeks in the contralateral (non-blast) eye, but not in the ipsilateral (blast) eye. A subsequent paradigm of 10 blasts of 20psi to the eye combined with 20 blasts of 50psi to the head (posterior to the eye), eliminated decreased retinal function but maintained damage to the ON. Immunolabeling of TNF-α, IL-1β, and GFAP was brighter in injured eyes compared to sham eyes. Blasts to the head (posterior to the eye) caused greater injury than blasts to the brow ridge (superior to the eye).
Conclusions :
Tree shrews require a higher blast level, a greater number of blasts, and a longer amount of time post-injury for TON compared to mice. This is likely due to the biomechanically more robust structural features in tree shrew compared to mouse and rat, including a collagenous load-bearing lamina cribrosa and protective bony brow ridge.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.