Toxic Mechanisms of Vesicating Chemicals in the Eye

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PROJECT SUMMARY/ABSTRACT The cornea is highly susceptible to injury from chemotoxic vapors. Long-term prognosis after severe corneal injury is poor, involving impaired vision, progressive corneal decompensation and neovascularization. In particular, ocular injuries caused by the formation of chemical adducts between biological molecules and highly reactive organic toxic industrial materials (TIMs) remain poorly characterized. The ocular threat caused by organic TIMs was illustrated in Bhopal, India in 1984, when the accidental release of methyl isocyanate resulted in over 3,700 deaths and 500,000 casualties, with 4,000 survivors suffering permanently disabling ocular pathophysiologies such as corneal scars, opacities and cataracts. In this proposal we will characterize the dose- dependent, acute and long-term effects of diverse, highly reactive organic TIMs on corneal injury and recovery. The approach integrates in vivo methods developed to study corneal toxicities elicited by the archetypal vesicant sulfur mustard with ex vivo approaches pioneered to study the corneal effects of exposure to diverse chemotoxic agents. We will focus on TIMs that are widely availability in large quantities and thus pose a large-scale chemotoxic threat following accidental or purposeful release. In the first aim, we will integrate the ex vivo depth- of-injury exposure model with our well-described vapor cap exposure system to determine TIM vapor doses that produce mild and severe corneal lesions in isolated rabbit eyes. In the second aim, we will translate dose estimates to in vivo eyes in rabbits and study molecular, clinical and pathophysiological mechanisms of corneal injury over 8 weeks. In the final aim, we will compare and contrast (a) acute changes in gene expression in human and rabbit eyes exposed to superficial and penetrating doses of three TIMs and (b) study longitudinal changes in gene expression in vivo following exposure to penetrating doses of 3 TIMs. By studying the toxic effects of diverse reactive TIMs, we will develop a threat profile based on dose, tissue-specific cytotoxicities, pathophysiological progression and efficacy of available therapeutics. In addition to identifying toxicological mechanisms and expanding our understanding of chemotoxic injury in the cornea, these studies will inform risk assessments and exposure management plans for these highly toxic organic TIMs and related chemicals.