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Pathogenesis of Acute and Delayed Corneal Lesions After Ocular Exposure to Sulfur Mustard Vapor

McNutt, Patrick PhD*; Hamilton, Tracey BS*; Nelson, Marian BS*; Adkins, Angela BA*; Swartz, Adam MS*; Lawrence, Richard BS*; Milhorn, Denise PhD†

doi: 10.1097/ICO.0B013E31823D02CD
Basic Investigation

Purpose: Sulfur mustard (SM) exposure results in dose-dependent morbidities caused by cytotoxicity and vesication. Although lesions resulting from ocular exposure often resolve clinically, an idiopathic delayed mustard gas keratopathy (MGK) can develop after a moderate or severe exposure. Sequelae include persistent keratitis, recurring epithelial lesions, corneal neovascularization, and corneal degeneration, which can lead to impaired vision or loss of sight. The purpose of this effort is to correlate structural changes with injury progression during the development of MGK.

Methods: New Zealand White rabbit corneas were exposed to SM using a vapor cup delivery system. The transition from acute to delayed injury was characterized by clinical, histological, and ultrastructural metrics over 8 weeks.

Results: Exposure dose was correlated to the likelihood of developing MGK but not to its severity. In a 56-animal cohort, a 2.5-minute exposure generated a corneal lesion, with 89% of corneas developing MGK within 5 weeks. A significant decrease in corneal edema at 2 weeks was predictive of the 11% of corneas that underwent asymptomatic recovery. Ultrastructural comparison of asymptomatic and MGK corneas at 8 weeks indicates that MGK is characterized by persistent edema and profound disorganization of the basement membrane zone.

Conclusions: Ultrastructural changes associated with the delayed pathophysiology of corneal SM vapor exposure involve severe degeneration of the basement membrane zone and persistent edema. The mechanisms underlying MGK pathogenesis seem to alter injury progression as soon as 2 weeks after exposure. These data suggest that the vapor cup model system is suitable for therapeutic evaluation.

From the *United States Army Medical Research Institute of Chemical Defense, Gunpowder, MD; and †United States Army Medical Research and Materiel Command, Fort Detrick, MD.

Received for publication June 23, 2011; revision received August 19, 2011; accepted August 24, 2011.

Supported by the Defense Threat Reduction Agency—Joint Science and Technology Office, Medical S&T Division (grant numbers 2.F0012_07_RC_C, CBM.CUTOC.01.10.RC.003).

The authors state that they have no financial or conflicts of interest to disclose.

The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, or the US Government. The experimental protocol was approved by the Animal Care and Use Committee at the United States Army Medical Research Institute of Chemical Defense, and all procedures were conducted in accordance with the principles stated in the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996), and the Animal Welfare Act of 1966 (P.L. 89-544), as amended.

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Reprints: Patrick McNutt, United States Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Rd, Gunpowder, MD 21010 (e-mail:

© 2012 Lippincott Williams & Wilkins, Inc.