Progression of ocular sulfur mustard injury: development of a model system

Abstract

Exposure of tissues to sulfur mustard (SM) results in the formation of protein and nucleotide adducts that disrupt cellular metabolism and cause cell death. Subsequent pathologies involve a significant proinflammatory response, disrupted healing, and long-term defects in tissue architecture. Following ocular exposure, acute corneal sequelae include epithelial erosions, necrosis, and corneal inflammation. Longer term, a progressive injury becomes distributed throughout the anterior chamber, which ultimately causes a profound remodeling of corneal tissues. In many cases, debilitating and vision-threatening injuries reoccur months to years after the initial exposure. Preliminary data in humans suffering from chronic epithelial lesions suggest that thymosin beta4 (Tbeta4) may be a viable candidate to mitigate acute or long-term ocular SM injury. To evaluate therapeutic candidates, we have developed a rabbit ocular exposure model system. In this paper, we report molecular, histological, ultrastructural, and clinical consequences of rabbit ocular SM injury, which can be used to assess Tbeta4 efficacy, including timepoints at which Tbeta4 will be assessed for therapeutic utility.

Clinical progression of ocular injury following arsenical vesicant lewisite exposure

“…The persistent neovascularization which remained elevated at 56 day post-exposure indicates oxygen deprivation as well as persistent inflammation and injury to the cornea causing loss of transparency and vision problems. Edema and corneal thickness are also reported following SM exposure, which peaked by 7 days post-exposure (10, 22-24), and consistent with that, corneal thickness was maximal at 1-7 days post LEW exposure indicating edema and inflammation. LEW at both 2.5 and 7.5 min exposure durations caused swelling and redness of the conjunctiva and iris, which resolved simultaneously at 4-14 days post-exposure; these injuries have been reported with both LEW and SM (10, 15, 22).…”

“…Edema and corneal thickness are also reported following SM exposure, which peaked by 7 days post-exposure (10, 22-24), and consistent with that, corneal thickness was maximal at 1-7 days post LEW exposure indicating edema and inflammation. LEW at both 2.5 and 7.5 min exposure durations caused swelling and redness of the conjunctiva and iris, which resolved simultaneously at 4-14 days post-exposure; these injuries have been reported with both LEW and SM (10, 15, 22). Importantly, though the gross features of LEW-induced ocular injury in the present study in rabbits were observed within 6 h post-exposure, these lesions in rabbits including corneal injuries were observed 24-48 h post SM exposure (21, 25).…”

“…As reported earlier by Mann et al, the current study also documents an immediate and early swelling and redness on eyelids, conjunctiva and iris of the eye, and edematous and opaque cornea at all the LEW exposure times (15). Studies with SM have shown that corneal ulceration peaks at 1-2 days post-exposure and then decreases by 4 days post-exposure (10, 21). Following LEW exposure in the present study, corneal ulceration also peaked at 1 day post-exposure; however, after decreasing till 7 day post-exposure, corneal ulceration recurred at 14 day post-LEW exposure.…”

Nitrogen Mustard-Induced Corneal Injury Involves DNA Damage and Pathways Related to Inflammation, Epithelial-Stromal Separation, and Neovascularization

“…Despite imminent threats and devastating ocular injuries by vesicating agents 6–11 , effective therapies suitable in case of a mass casualty are not established. This is primarily due to the lack of defined mechanisms contributing to pathological and clinical progression of ocular injuries by vesicants in relevant animal models.…”

Ocular Toxicity of Chemical Warfare Agents

“…The rabbit cornea is structurally similar to that of the human, and at functionally equivalent doses, rabbit and human eyes exhibit nearly identical lesions (Mann and Pullinger, 1944;Gates and Moore, 1946). Recently, a rabbit vapor HD exposure model has been shown to produce dose-dependent, multiphasic corneal injuries with sequelae similar to those observed in human victims (Kadar et al, 2001;Milhorn et al, 2010;McNutt et al, 2012a,b).…”