Corneal toxicity induced by vesicating agents and effective treatment options

Abstract

The vesicating agents sulfur mustard (SM) and lewisite (LEW) are potent chemical warfare agents that primarily cause damage to the ocular, skin, and respiratory systems. However, ocular tissue is the most sensitive organ, and vesicant exposure results in a biphasic injury response, including photophobia, corneal lesions, corneal edema, ulceration, and neovascularization, and may cause loss of vision. There are several reports on ocular injury from exposure to SM, which has been frequently used in warfare. However, there are very few reports on ocular injury by LEW, which indicate that injury symptoms appear instantly after exposure and faster than SM. In spite of extensive research efforts, effective therapies for vesicant-induced ocular injuries, mainly to the most affected corneal tissue, are not available. Hence, we have established primary human corneal epithelial (HCE) cells and rabbit corneal organ culture models with the SM analog nitrogen mustard (NM), which have helped to test the efficacy of potential therapeutic agents. These agents will then be further evaluated against in vivo SM- and LEW-induced corneal injury models, which will assist in the development of potential broad-spectrum therapies against vesicant-induced ocular injuries.

Nitrogen mustard-induced corneal injury involves the sphingomyelin-ceramide pathway

“…Usually, an acute phase occurs initially, manifesting clinically as photophobia, inflammation of the anterior segment, and corneal erosions. This may be followed by irreversible corneal injuries that progress to vision impairment and, potentially, blindness [11].…”

Phosgene oxime: Injury and associated mechanisms compared to vesicating agents sulfur mustard and lewisite

“…Eyes are the most sensitive organ to vesicant exposure (Ghasemi et al, 2013; Gordon et al, 2009; Goswami et al, 2016a; Kadar et al, 2013a; Kadar et al, 2009; Kadar et al, 2013b; McNutt et al, 2012; Tewari-Singh et al, 2016). CX exposure of the eye results in immediate and severe pain, irritation, edema, lacrimation, conjunctivitis, and blepharospasm with more severe exposure resulting in keratitis, iritis, corneal perforation and blindness (Table 2) (Patocka, 2011).…”

“…Among vesicating agents, effective anti-dotes are available only for LEW-induced toxicity, in the form of British Anti-Lewisite (BAL; dimercaprol) and derivatives, meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-1-propane- sulphonic acid (DMPS) (Goswami et al, 2016a; Hughes, 1946, 1947; Mann et al, 1947; Mouret et al, 2013). However, there are still limitations with the use of these therapies including narrow therapeutic window, toxicity and difficulty in administration, thus, requiring the need for the development of better and safe antidotes.…”

“…There are no effective approved antidotes available for SM. Although a number of compounds including anti-oxidants, protease inhibitors, PARP inhibitors, angiogenesis inhibitors, calcium modulators, anti-inflammatory agents, and flavanones have been shown to be effective to various extents in laboratory studies (Balszuweit et al, 2013; Goswami et al, 2016a; Kadar et al, 2014; Kadar et al, 2009; Laskin et al, 2010; McElroy and Day, 2016; Paromov et al, 2007; Smith, 2009; Tewari-Singh and Agarwal, 2016; Weinberger et al, 2016). There is no specific antidote available against CX-induced injuries and the treatment is mostly supportive to reduce symptoms, prevent infections and help healing.…”

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

“…Increasing evidence indicates stromal and endothelial cell damage also occurs at the time of the original insult, and the extent of the injuries to these more posterior layers may be related to the onset of the chronic disease that is seen in more severely affected casualties. 3 Steroids, such as dexamethasone, have had limited use in treating the acute phase damage to the epithelial layer after mustard exposure, 4 which will generally heal itself in a few weeks with no intervention, 5 , 6 and organ transplants remain the only effective treatment for the chronic phase of the disease, generally known as mustard gas keratopathy (MGK). 7 , 8 SM is clearly more toxic than NM, and the knowledge base of vesicant effects is mainly derived from its study; however, NM, which is more amenable to laboratory manipulations, shows sufficiently similar responses by epithelial cells to be a useful paradigm for testing potential protective agents against vesicant damage.…”