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

McNutt, Patrick; Hamilton, Tracey A.; Nelson, Marian; Adkins, Angela L.; Swartz, Adam; Lawrence, Richard J.; Milhorn, Denise

doi:10.1097/ico.0b013e31823d02cd

Cited by 63 publications

(72 citation statements)

References 23 publications

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“…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).…”

Section: Discussionsupporting

confidence: 82%

Clinical progression of ocular injury following arsenical vesicant lewisite exposure

Tewari‐Singh

Croutch

Tuttle

et al. 2016

Cutaneous and Ocular Toxicology

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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.

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Section: Discussionsupporting

confidence: 82%

Clinical progression of ocular injury following arsenical vesicant lewisite exposure

Tewari‐Singh

Croutch

Tuttle

et al. 2016

Cutaneous and Ocular Toxicology

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“…Depending on dose, inflammation and edema are observed as well as increasing corneal thickness, and sloughing of epithelial cells. Detachment of epithelial cells is thought to be due to degradation of the basement membrane and basal cell hemidesmosome transmembraneous components, which are critical for the attachment of the epithelium to the basement membrane (Petrali et al , 1997; McNutt et al , 2012; Kadar et al , 2013). Our laboratories have been characterizing the effects of ocular toxicants including UVB and vesicants on rabbit cornea using an air-lifted organ culture model (Gordon et al , 2010).…”

Section: Discussionmentioning

confidence: 99%

The generation of 4-hydroxynonenal, an electrophilic lipid peroxidation end product, in rabbit cornea organ cultures treated with UVB light and nitrogen mustard

Zheng

Mishin

et al. 2013

Toxicology and Applied Pharmacology

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The cornea is highly sensitive to oxidative stress, a process that can lead to lipid peroxidation. Ultraviolet light B (UVB) and nitrogen mustard (mechlorethamine) are corneal toxicants known to induce oxidative stress. Using a rabbit air-lifted corneal organ culture model, the oxidative stress responses to these toxicants in the corneal epithelium was characterized. Treatment of the cornea with UVB (0.5 J/cm2) or nitrogen mustard (100 nmol) resulted in the generation of 4-hydroxynonenal (4-HNE), a reactive lipid peroxidation end product. This was associated with increased expression of the antioxidant, heme oxygenase-1 (HO-1). In human corneal epithelial cells in culture, addition of 4-HNE or 9-nitrooleic acid, a reactive nitrolipid formed during nitrosative stress, caused a time-dependent induction of HO-1 mRNA and protein; maximal responses were evident after 10 hr with 30 μM 4-HNE or 6 hr with 10 μM 9-nitrooleic acid. 4-HNE and 9-nitrooleic acid were also found to activate Erk1/2, JNK and p38 MAP kinases, as well as phosphoinositide-3-kinase (PI3)/Akt. Inhibition of p38 blocked 4-HNE- and 9-nitrooleic acid-induced HO-1 expression. Inhibition of Erk1/2, and to a lesser extent, JNK and PI3K/Akt, suppressed only 4-HNE-induced HO-1, while inhibition of JNK and PI3K/Akt, but not Erk1/2, partly reduced 9-nitrooleic acid-induced HO-1. These data indicate that the actions of 4-HNE and 9-nitrooleic acid on corneal epithelial cells are distinct. The sensitivity of corneal epithelial cells to oxidative stress may be an important mechanism mediating tissue injury induced by UVB or nitrogen mustard.

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“…These studies provide insight and have improved treatment for patients whose corneas have been injured by chemicals (Fish and Davidson, 2010; Javadi et al, 2005; Khaw et al, 2004; Saika, 2007; Sosne et al, 2002). In addition, studies are now being carried out to better understand and treat the corneal pathology seen in response to nerve gas treatment (Gordon et al, 2010; McNutt et al, 2012). The most frequently used model to study the corneas response to chemical injury involves soaking circular filters in 0.15M NaOH (Bargagna-Mohan et al, 2012; Lee et al, 2013).…”

Section: Variations In Wound Typesmentioning

confidence: 99%

Wounding the cornea to learn how it heals

Stepp

Zieske

Trinkaus‐Randall

et al. 2014

Experimental Eye Research

133

128

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Corneal wound healing studies have a long history and rich literature that describes the data obtained over the past 70 years using many different species of animals and methods of injury. These studies have lead to reduced suffering and provided clues to treatments that are now helping patients live more productive lives. In spite of the progress made, further research is required since blindness and reduced quality of life due to corneal scarring still happens. The purpose of this review is to summarize what is known about different types of wound and animal models used to study corneal wound healing. The subject of corneal wound healing is broad and includes chemical and mechanical wound models. This review focuses on mechanical injury models involving debridement and keratectomy wounds to reflect the authors’ expertise.

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

Cited by 63 publications

References 23 publications

Clinical progression of ocular injury following arsenical vesicant lewisite exposure

Clinical progression of ocular injury following arsenical vesicant lewisite exposure

The generation of 4-hydroxynonenal, an electrophilic lipid peroxidation end product, in rabbit cornea organ cultures treated with UVB light and nitrogen mustard

Wounding the cornea to learn how it heals

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