Contributions of tissue‐specific pathologies to corneal injuries following exposure to SM vapor

McNutt, Patrick; Tuznik, Kaylie; Glotfelty, Elliot J.; Nelson, Marian; Lyman, Megan; Hamilton, Tracey A.

doi:10.1111/nyas.13105

Cited by 16 publications

(5 citation statements)

References 51 publications

(161 reference statements)

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“…Previous reports strongly indicate the alkylating effects of SM on ocular biomolecules, which may lead to inflammation, corneal degradation, and delayed LSCD and contribute to the pathogenesis of vesicant-induced ocular toxicity [ 16 , 25 , 48 ]. SM exposure is reported to induce histopathological changes including vesication, ulceration, keratocyte cell death, ocular inflammation, and NV [ 29 , 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

Pathophysiology and inflammatory biomarkers of sulfur mustard-induced corneal injury in rabbits

et al. 2021

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Sulfur mustard (SM) is a cytotoxic, vesicating, chemical warfare agent, first used in 1917; corneas are particularly vulnerable to SM exposure. They may develop inflammation, ulceration, neovascularization (NV), impaired vision, and partial/complete blindness depending upon the concentration of SM, exposure duration, and bio-physiological conditions of the eyes. Comprehensive in vivo studies have established ocular structural alterations, opacity, NV, and inflammation upon short durations (<4 min) of SM exposure. In this study, detailed analyses of histopathological alterations in corneal structure, keratocytes, inflammatory cells, blood vessels, and expressions of cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-9, vascular endothelial growth factor (VEGF), and cytokines were performed in New Zealand white rabbits, in a time-dependent manner till 28 days, post longer durations (5 and 7 min) of ocular SM exposure to establish quantifiable endpoints of injury and healing. Results indicated that SM exposure led to duration-dependent increases in corneal thickness, opacity, ulceration, epithelial-stromal separation, and epithelial degradation. Significant increases in NV, keratocyte death, blood vessels, and inflammatory markers (COX-2, MMP-9, VEGF, and interleukin-8) were also observed for both exposure durations compared to the controls. Collectively, these findings would benefit in temporal delineation of mechanisms underlying SM-induced corneal toxicity and provide models for testing therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Pathophysiology and inflammatory biomarkers of sulfur mustard-induced corneal injury in rabbits

et al. 2021

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“…Indeed, the development of the chronic problems of mustard gas injury, or MGK, seems to be at least in part dependent on the extent of damage incurred by the endothelial cell layer during the acute phase of the insult. 32 , 33 There is certainly epithelial cell loss that occurs during this period (up to 2 days) that results from the modification of proteins/nucleic acids essential for viability.…”

Section: Discussionmentioning

confidence: 99%

An Engineered Human Fibroblast Growth Factor-1 Derivative, TTHX1114, Ameliorates Short-term Corneal Nitrogen Mustard Injury in Rabbit Organ Cultures

Eveleth

Subramaniam

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeOrgan cultures of rabbit corneas have been used to ascertain the effectiveness of a human fibroblast growth factor (FGF)-1 derivative (TTHX1114), lacking cysteine residues, to protect against and/or repair epithelial lesions following exposure to nitrogen mustard (NM).MethodsRabbit corneas were exposed to NM and cultured for up to 14 days, with or without drug (TTHX1114). At specified times, tissue was examined by histopathology and graded by a novel composite scale. Proliferation was measured by 5-ethynyl-2′-deoxyuridine (EdU) incorporation, and the expression of native FGF-1 and ADAM-17 after NM exposure was determined by immunofluorescence.ResultsRabbit corneas, exposed to a single dose of NM, showed a nearly complete loss of epithelial cells by day 6 but were significantly regenerated by day 14. When treated continuously with TTHX1114 following vesicant exposure, the losses remained at day 2 levels. The loss of keratocytes in the stroma was not affected by TTHX1114. EdU incorporation over the same time course showed a steady increase in tissue that had not been treated with TTHX1114, while corneas that were treated with the drug showed a higher percent incorporation initially, which then decreased, indicating the strong proliferative response to TTHX1114. ADAM-17 was not significantly altered by TTHX1114 treatment. Corneal epithelial FGF-1 disappeared after only 1 day following exposure to NM.ConclusionsTTHX1114 is protective against NM-induced damage of the corneal epithelium, possibly by supplying an NM-resistant source of trophic support and by stimulating regeneration of new epithelial cells. These responses underscore the potential value of TTHX1114 as an anti-vesicant therapeutic.

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“…Compared with other ocular surface tissues, the corneal epithelium and endothelium are more susceptible to mustard gas injury than the stroma. 18 Persistent inflammation also contributes to late ocular complications, collectively termed mustard gas keratopathy. 19 Corneal stromal scarring and neovascularization, neurotrophic keratitis, corneal edema, and limbal stem cell deficiency are observed in the late stage.…”

Section: Clinical Course and Current Management Of Corneal Injuriesmentioning

confidence: 99%

“… 19 Corneal stromal scarring and neovascularization, neurotrophic keratitis, corneal edema, and limbal stem cell deficiency are observed in the late stage. 18 – 21 …”

Section: Clinical Course and Current Management Of Corneal Injuriesmentioning

confidence: 99%

Therapeutic Potential of Extracellular Vesicles for the Treatment of Corneal Injuries and Scars

Deng

Santos

Gee

2020

Trans. Vis. Sci. Tech.

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Infection, trauma, and chemical exposure of the ocular surface can severely damage the cornea, resulting in visually significant stromal scars. Current medical treatments are ineffective in mitigating corneal scarring, and corneal transplantation is the only therapy able to restore vision in these eyes. However, because of a severe shortage of corneal tissues, risks of blinding complications associated with corneal transplants, and a higher rate of graft failure in these eyes, an effective and deliverable alternative therapy for the prevention and treatment of corneal scarring remains a significant unmet medical need globally. In recent years, the therapeutic potential of extracellular vesicles (EVs) secreted by cells to mediate cell-cell communication has been a topic of increasing interest. EVs derived from mesenchymal stem cells, in particular human corneal stromal stem cells, have antifibrotic, anti-inflammatory, and regenerative effects in injured corneas. The exact mechanism of action of these functional EVs are largely unknown. Therapeutic development of EVs is at an early stage and warrants further preclinical studies.

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Contributions of tissue‐specific pathologies to corneal injuries following exposure to SM vapor

Cited by 16 publications

References 51 publications

Pathophysiology and inflammatory biomarkers of sulfur mustard-induced corneal injury in rabbits

Pathophysiology and inflammatory biomarkers of sulfur mustard-induced corneal injury in rabbits

An Engineered Human Fibroblast Growth Factor-1 Derivative, TTHX1114, Ameliorates Short-term Corneal Nitrogen Mustard Injury in Rabbit Organ Cultures

Therapeutic Potential of Extracellular Vesicles for the Treatment of Corneal Injuries and Scars

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