Ocular injuries following sulfur mustard exposure—Pathological mechanism and potential therapy

Kadar, Tamar; Dachir, Shlomit; Cohen, Liron; Sahar, Rita; Fishbine, Eliezer; Cohen, Maayan; Turetz, J.; Gutman, Hila; Buch, Hillel; Brandeis, Rachel; Horwitz, Vered; Solomon, Abraham; Amir, Adina

doi:10.1016/j.tox.2008.10.026

Cited by 118 publications

(129 citation statements)

References 55 publications

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“…8), as previously reported. 15 The doxycycline hydrogels produced the same improvement in corneal clarity. Edema adversely affects transparency by increasing the corneal thickness, which was assessed by pachymetry.…”

Section: Doxycycline Drops and Hydrogels Ameliorate Sm Injury Of In Vmentioning

confidence: 86%

“…Although not a perfect therapy, the MMP inhibitor and antibiotic, doxycycline, improves healing of SM-exposed corneas 15 and lungs. 21 Therefore, we asked whether other tetracycline derivatives would be equally or more effective as corneal therapies for vesicants.…”

Section: Evaluation Of Tetracycline Derivatives As Therapies For Vesimentioning

confidence: 99%

“…Such corneal organ culture models have been used for wound healing studies and have been tested for epithelial, endothelial, and stromal cell viability under a variety of conditions. 13,14 The recent report evaluating healing of rabbit eyes exposed in vivo to SM followed by treatment with the tetracycline derivative doxycycline 15 suggested that tetracyclines in general might be useful therapies. Here we show that corneal organ cultures can be used for the preliminary evaluations of drugs.…”

mentioning

confidence: 99%

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Doxycycline Hydrogels as a Potential Therapy for Ocular Vesicant Injury

Gordon

Desantis

Deshmukh

et al. 2010

Journal of Ocular Pharmacology and Therapeutics

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Purpose: The goals of this study were (1) to compare the injury at the basement membrane zone (BMZ) of rabbit corneal organ cultures exposed to half mustard (2 chloroethyl ethyl sulfide, CEES) and nitrogen mustard with that of in vivo rabbit eyes exposed to sulfur mustard (SM); (2) to test the efficacy of 4 tetracycline derivatives in attenuating vesicant-induced BMZ disruption in the 24-h period postexposure; and (3) to use the most effective tetracycline derivative to compare the improvement of injury when the drug is delivered as drops or hydrogels to eyes exposed in vivo to SM. Methods: Histological analysis of hematoxylin and eosin-stained sections was performed; the ultrastructure of the corneal BMZ was evaluated by transmission electron microscopy; matrix metalloproteinase-9 was assessed by immunofluorescence; doxycycline as drops or a hydrogel was applied daily for 28 days to eyes exposed in vivo to SM. Corneal edema was assessed by pachymetry and the extent of neovascularization was graded by length of longest vessel in each quadrant. Results: Injury to the BMZ was highly similar with all vesicants, but varied in degree of severity. The effectiveness of the 4 drugs in retaining BMZ integrity did not correlate with their ability to attenuate matrix metalloproteinase-9 expression at the epithelial-stromal border. Doxycycline was most effective on organ cultures; therefore, it was applied as drops or a hydrogel to rabbit corneas exposed in vivo to SM. Eyes were examined at 1, 3, 7, and 28 days after exposure. At 7 and 28 days after SM exposure, eyes treated with doxycycline were greatly improved over those that received no therapy. Corneal thickness decreased somewhat faster using doxycycline drops, whereas the hydrogel formulation decreased the incidence of neovascularization. Conclusions: Corneal cultures exposed to 2-chloroethyl ethyl sulfide and nitrogen mustard were effective models to simulate in vivo SM exposures. Doxycycline as drops and hydrogels ameliorated vesicant injury. With in vivo exposed animals, the drops reduced edema faster than the hydrogels, but use of the hydrogels significantly reduced neovascularization. The data provide proof of principle that a hydrogel formulation of doxycycline as a daily therapy for ocular vesicant injury should be further investigated.

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Section: Doxycycline Drops and Hydrogels Ameliorate Sm Injury Of In Vmentioning

confidence: 86%

Section: Evaluation Of Tetracycline Derivatives As Therapies For Vesimentioning

confidence: 99%

mentioning

confidence: 99%

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Doxycycline Hydrogels as a Potential Therapy for Ocular Vesicant Injury

Gordon

Desantis

Deshmukh

et al. 2010

Journal of Ocular Pharmacology and Therapeutics

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“…topical corticosteroids may be useful to both minimize discomfort and to control the inflammatory component of lScs and may help in the regression of corneal neovascularization. 58 antivascular endothelial growth factor (anti-veGF) agents such as bevacizumab may also prove beneficial in the management of corneal neovascularization, secondary to lScD; however, early anti-veGF therapy may impair the Sc (our unpublished data). amniotic membrane transplantation alone without Sc was sufficient for treatment of lScD, in patients receiving 5-FU after glaucoma filtering surgery.…”

Section: Management Of the Delayed-onset Lscdmentioning

confidence: 94%

“…as chronic inflammation is involved in most cases, then a postexposure prophylactic treatment with antiinflammatory drugs would probably be beneficial in reducing the rate of lScD, as indeed was shown by our group for Sm keratopathy in the rabbit model. 55,58 it is important to distinguish between total and partial lScD. For mild symptoms, conservative management with preservative-free artificial tears, due to tear dysfunction, may be sufficient.…”

Section: Management Of the Delayed-onset Lscdmentioning

confidence: 99%

Delayed Development of Limbal Stem Cell Deficiency Following Chemical Injury—Pathogenesis and Therapeutic Strategies

Kadar¹,

Dachir²,

Horwitz³

et al. 2013

US Ophthalmic Review

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Limbal epithelial stem cell deficiency (LSCD) occurs as a result of damage to the limbal epithelial stem cells (ESC) population. It may derive from direct destructive loss of the ESC (common chemical burn), and/or from dysfunction of the SC niche, leading to delayed death of the cells. This review focuses on delayed-onset LSCD, induced by antineoplastic chemicals, such as mitomycin C, 5-fluorouracil, and mustards, in terms of pathogenesis and management. These agents are used in ocular surface chemotherapy, in ocular surgery procedures, and as warfare agents, and target proliferating cells as slow-cycling cells, such as the ESC, are relatively resistant. Although the mechanism of the delayed loss of ESC is not entirely clear, we have shown, in the rabbit model, pathologic alterations in the limbal stroma, following the application of sulfur mustard, suggesting that dysfunction of the niche triggers the death of the SC later on. The absence of direct cytotoxic effects of these agents on the ESC, indicates a therapeutic window for prevention of the delayed LSCD.

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Ocular Effects of Sulfur Mustard and Therapeutic Approaches

Panahi

Rajaee

Sahebkar

2017

J of Cellular Biochemistry

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Sulfur mustard (SM) is a strong blistering, highly reactive, lipophilic chemical war agent that causes injury in different organs including the skin, eyes, and respiratory tract. The Eyes are especially susceptible to the consequences of SM poisoning because of the aqueous and mucosal nature of conjunctiva and cornea. DNA alkylation and depletion of glutathione, are the most important mechanisms of SM action in the eye injuries. Acute clinical symptoms are including decrease in visual acuity, dryness, photophobia, blepharospasm, conjunctivitis, and complaints of foreign body sensation and soreness that gradually progress to severe ocular pain. Corneal abrasions, ulcerations, vesication, and perforations are common corneal consequences in SM injured victims. Appearance of chronic symptoms has been reported as chronic inflammation of the corneal and conjunctival vasculature, ischemia, lipid and cholesterol deposition, scarring in cornea, corneal thinning, opacification and perforation of the cornea, limbal stem cell deficiency (LSCD), and neovascularization. Different medical and surgical protocols have been documented in the management of SM-induced ocular injuries, including preservative-free artificial tears, topical steroids and antibiotic, mydriatic, antiglaucoma drops, therapeutic contact lenses, dark glasses and punctal plugs/cauterization, N-acetylcysteine, tarsorrhaphy, amniotic membrane transplantation, stem cell transplantation, and corneal transplantation. New drugs such as resolvin E1, topical form of essential fatty acids, thymosin β4, 43 amino-acid polypeptides, topical form of curcumin, newly formulated artificial tears, diquafosol, rebamipide, tretinoin, and oral uridineseems to be beneficial in the management of ocular lesion associated with sulfur mustard poisoning. Further studies are needed to approve these drugs in SM victims. J. Cell. Biochem. 118: 3549-3560, 2017. © 2017 Wiley Periodicals, Inc.

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Ocular injuries following sulfur mustard exposure—Pathological mechanism and potential therapy

Cited by 118 publications

References 55 publications

Doxycycline Hydrogels as a Potential Therapy for Ocular Vesicant Injury

Doxycycline Hydrogels as a Potential Therapy for Ocular Vesicant Injury

Delayed Development of Limbal Stem Cell Deficiency Following Chemical Injury—Pathogenesis and Therapeutic Strategies

Ocular Effects of Sulfur Mustard and Therapeutic Approaches

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