Ocular injuries following sulfur mustard exposure--pathological mechanism and potential therapy.
Sulfur mustard (SM) is a potent vesicant, known for its ability to cause incapacitation and prolonged injuries to the eyes, skin and respiratory system. The toxic ocular events following sulfur mustard exposure are characterized by several stages: photophobia starting a few hours after exposure, an acute injury phase characterized by inflammation of the anterior segment and corneal erosions and a delayed phase appearing following a clinically silent period (years in human). The late injury appeared in part of the exposed eyes, expressed by epithelial defects and corneal neovascularization (NV), that lead to vision deficits and even blindness. During the last years we have characterized the temporal development of ocular lesions following SM vapor exposure in rabbits and have shown the existence of two sub-populations of corneas, those exhibiting delayed ocular lesions (clinically impaired) and those exhibiting only minor injuries if at all (clinically non-impaired). The aim of the present study was to investigate the pathological mechanism underlying the delayed injury by focusing on the unique characteristics of each sub-population and to test the efficacy of potential treatments. Clinically impaired corneas were characterized by chronic inflammation, increased matrix metalloproteinase (MMP) activity, poor innervation and limbal damage. Moreover, using impression cytology and histology, we identified the delayed lesions as typical for an ocular surface disorder under the category of limbal epithelial stem cell deficiency (LSCD). These results point to therapeutic directions, using anti-inflammatory drugs, MMPs inhibitors, neurotrophic factors and amniotic membrane transplantation. Topical anti-inflammatory drugs, either steroid (Dexamycin, DEX) or non-steroidal anti-infllammatory drug (NSAID, Voltaren Ophtha) were found to be beneficial in ameliorating the initial inflammatory response and in postponing the development of corneal NV, when given during the first week after exposure. When DEX was administered as a symptomatic treatment against NV, a significant regression in the angiogenic process was observed, however, the effect was temporal and blood vessels reappeared after therapy ceased. Chronic administration (8 weeks) of the MMP inhibitor Doxycycline was also effective in attenuation of the acute and delayed injury. Preliminary results, using amniotic membrane transplantation revealed some decrease of corneal edema with no effect on corneal NV. It is suggested that the chronic inflammation and prolonged impairment of corneal innervation are playing a role in the pathogenesis of the delayed LSCD following SM exposure by creating a pathological microenvironment to limbal epithelial stem cells, thus, leading to their slow death and to a second cascade of pathological events eventually resulting in severe long-term injuries. As of today, only topical anti-inflammatory drugs reached the criteria of an applicable efficient post-exposure ocular treatment for SM injuries. Further studies are required to investigate the effects of SM on epithelial stem cells and their involvement in the pathogenesis of the long-term injuries.
Kadar
Tamar
T
Department of Pharmacology, Israel Institute for Biological Research, Ness-Ziona 74100, Israel. tamark@iibr.gov.il
Dachir
Shlomit
S
Cohen
Liat
L
Sahar
Rita
R
Fishbine
Eliezer
E
Cohen
Maayan
M
Turetz
Joseph
J
Gutman
Hila
H
Buch
Hillel
H
Brandeis
Rachel
R
Horwitz
Vered
V
Solomon
Abraham
A
Amir
Adina
A
D053687:Adult Stem Cells / Q000187:drug effects / Q000473:pathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002619:Chemical Warfare Agents / Q000633:toxicity*; D003316:Corneal Diseases / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D015715:Corneal Edema / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D016510:Corneal Neovascularization; D003318:Corneal Opacity / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007322:Instillation, Drug; D016850:Limbus Corneae / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D061965:Matrix Metalloproteinase Inhibitors; D009151:Mustard Gas / Q000633:toxicity*; D009355:Neomycin / Q000494:pharmacology; D011817:Rabbits
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002619:Chemical Warfare Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D003907:Dexamethasone; D009355:Neomycin; D004318:Doxycycline; D009151:Mustard Gas