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D. M. Milhorn, T. Hamilton, G. Sosne, P. McNutt; Development of a Rabbit Model System to Evaluate Therapeutic Strategies for Ocular Sulfur Mustard Injury. Invest. Ophthalmol. Vis. Sci. 2010;51(13):385.
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Ocular Sulfur Mustard (SM) exposure causes acute injury through the formation of protein and nucleotide adducts, resulting in cell death. Initially, exposure causes eye pain, photophobia, tearing, and blurred vision within hours. Over the following days, a progressive inflammatory injury is induced, which ultimately causes the remodeling of corneal tissue. Profound lesions reappear months to years after exposure. There are currently no therapies for SM ocular injuries. Our purpose is to establish an experimentally tractable rabbit model system for the assessment of therapeutic approaches, with the following objectives: 1) to identify reproducible metrics to characterize injury progression, 2) to evaluate whether injury in the rabbit ocular model system is commensurate with human ocular exposure, and 3) to correlate molecular, histological, ultrastructural, and clinical aspects of SM injury.
The corneas of anesthetized rabbits were exposed to SM vapor for 2.5 min using a vapor cup delivery system. Animals were evaluated with clinical metrics, such as fluorescein staining, pachymetry, slit lamp and gross observation; histopathological metrics such as transmission electron microscopy (TEM) and H&E staining; and longitudinal biochemical analysis of aqueous humor (AH).
The cornea re-epithelializes during the first week of exposure, followed by a clinically refractory period. The majority of exposed eyes then experience a recurrent, progressive injury starting around week 4. While the initial injury is restricted to the anterior tissues, the recurring injury is associated with significant architectural disruption throughout the anterior chamber. This remodeling is correlated with- and may be the consequence of- increased activity of pro-inflammatory mediators and matrix-active enzymes in AH during the recurrent phase.
Acute SM injury is well characterized; however the underlying causes of long-term corneal pathologies are still unknown. Our data suggests that persistent disruption of epithelial adhesion or endothelial barrier dysfunction in exposed corneas may provide a partial explanation for long-term pathologies such as recurrent epithelial erosions. Future studies will focus on determining critical points of therapeutic intervention and the efficacy of specific treatments.
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