Clinical progression of ocular injury following arsenical vesicant lewisite exposure

Abstract

Ocular injury by lewisite (LEW), a potential chemical warfare and terrorist agent, results in edema of eyelids, inflammation, massive corneal necrosis, and blindness. To enable screening of effective therapeutics to treat ocular injury from LEW, useful clinically-relevant endpoints are essential. Hence, we designed an efficient exposure system capable of exposing up to six New-Zealand white rabbits at one time, and assessed LEW vapor-induced progression of clinical ocular lesions mainly in the cornea. The right eye of each rabbit was exposed to LEW (0.2 mg/L) vapor for 2.5, 5.0, 7.5 and 10.0 min and clinical progression of injury was observed for 28 days post-exposure (dose-response study), or exposed to same LEW dose for 2.5 and 7.5 min and clinical progression of injury was observed for up to 56 days post-exposure (time-response study); left eye served as an unexposed control. Increasing LEW exposure caused corneal opacity within 6 h post-exposure, which increased up to 3 days, slightly reduced thereafter till 3 weeks, and again increased thereafter. LEW-induced corneal ulceration peaked at 1 day post-exposure and its increase thereafter was observed in phases. LEW exposure induced neovascularization starting at 7 days which peaked at 22-35 days post-exposure, and remained persistent thereafter. In addition, LEW exposure caused corneal thickness, iris redness, and redness and swelling of the conjunctiva. Together, these findings provide clinical sequelae of ocular injury following LEW exposure and for the first time establish clinically-relevant quantitative endpoints, to enable the further identification of histopathological and molecular events involved in LEW-induced ocular injury.

Biological and environmental hazards associated with exposure to chemical warfare agents: arsenicals

“…A recent study was performed in a rabbit model for the screening of effective therapeutics to treat ocular injury and to develop clinically relevant end points. Ocular injury caused by Lewisite resulted in edema of the eyelids, inflammation, massive corneal necrosis, and blindness, which was similar to that reported in humans . The single vapor exposure of Lewisite to the eye of New Zealand white rabbits induced clinical ocular lesions, mainly in the cornea.…”

“…These alterations were associated with neovascularization, which could be visualized at day 7, peaked between days 22 and 35, and remained persistent thereafter. Lewisite also caused corneal thickness, iris redness, and redness and swelling of the conjunctiva …”

Corneal toxicity induced by vesicating agents and effective treatment options

“…Unlike SM, LEW exposure results in an immediate irritation, inflammation of the eyes, and swelling of the eyelids . The findings from our recent study for the first time showed clinical sequelae of ocular injury following LEW exposure, including corneal wounding, ulceration, inflammation, neovascularization, corneal thickness, iris redness, and redness and swelling of the conjunctiva, and their progression up to 56 days postexposure . Importantly, LEW exposure in humans is shown to result in swelling and edema, inflammation to the iris and conjunctiva, and corneal damage; the injuries are similar to those observed in the rabbit model in our study, suggesting the relevance of the model developed by us for both mechanistic and efficacy studies in the future.…”

“…Importantly, LEW has not been studied as extensively as SM; therefore, useful end points are required for screening and development of effective therapies. Hence, in collaboration with MRIGlobal®, we have designed an efficient exposure system capable of exposing up to six rabbits at one time, with the ability to adjust both time and dose of vesicants . In this exposure system, the left eye of the rabbit serves as a control and is exposed to dilution air, while the right eye is simultaneously exposed to LEW or SM.…”

“…Modified goggles with flow‐through design were used for exposures. Using this consistent and efficient exposure system, we successfully carried out LEW exposures and established clinically relevant end points in a dose‐ and time‐response study . Unlike SM, LEW exposure results in an immediate irritation, inflammation of the eyes, and swelling of the eyelids .…”