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Evaluation of protease Inhibitors in sulfur mustard ocular injuries

TitleEvaluation of protease Inhibitors in sulfur mustard ocular injuries
Publication TypeConference Proceedings
Year of Conference2004
AuthorsAmir A., Turetz J., Brandeis R., Dachir S., Cohen L., Cohen M., Fishbeine E., Sahar R., Kadar T., Schultz G.
Conference NameProceedings of the U.S. Army Medical Defense Bioscience Review
Conference LocationAberdeen Proving Ground, MD

Sulfur mustard (HD) causes severe short and long- term ocular injuries leading to irreversible visual impairment and even blindness. Changes in matrix metalloprotease (MMP) activity, were shown to occur in the acute phase of skin lesion following HD exposure. Prevention of the HD induced dermal-epidermal separation was achieved by MMP inhibitor treatment (MMPI). Thus, it was assumed that MMPI treatment might decrease the severity of the acute HD induced ocular lesion as well. Moreover, MMPs are also implicated in the development of corneal neovascularization (NV), thus it was further assumed that MMPI’s could decrease the extent of NV, which is a major problem in the long-term ocular HD injury. The objective of this study was to assess the effects of the MMPIs Ilomastat (IL) and Doxycycline (DOX) on rabbit corneas following exposure to HD vapor, in comparison to the effects of the serine protease inhibitor alpha-1 protease inhibitor (α1-PI).Rabbit eyes were exposed for 4 minutes to HD vapor as described previously. Six experimental groups were assigned: 1.) HD control (no treatment); 2.) IL; 3.) α1-PI; 4.) DOX; 5.) combined treatment IL+ α1-PI, and 6.) combined treatment DOX+ α1-PI. Each group consisted of 6 rabbits. Treatments (topical, 50ul/eye) were started 15 minutes after exposure to HD, x4/day, six days/week, for 8 weeks. Eyes were evaluated daily during the first 4 days after exposure and once a week thereafter for 12 weeks. The severity of the clinical ocular symptoms was evaluated and scored as described previously.At the acute phase all the treated groups were at least by 10-20% less damaged than the untreated HD group. The significant beneficial effect of treatments was noted for inflammatory aspects of the lesion, the effect on corneal erosions was ns. At 1-2 weeks after the exposure, ocular healing was better in the IL and DOX treatment groups compared to the HD group, or the α1-PI containing groups, and IL scored better than DOX. However even in the αPI containing treatment groups, lesions were 50-70% smaller compared to HD group. The late phase lesion started typically in the HD group two weeks following exposure. IL or DOX treatments caused a significant reduction of corneal neovascularization (NV), the most conspicuous and detrimental aspect of the lesion. The lesion in all treatment groups containing αPI was similar to the untreated HD group. After the cessation of treatment, during the last 4 weeks of observations, the ocular lesion slightly increased in the IL and DOX groups.In summary, both Ilomastat and Doxycycline treatments exhibited a significant beneficial effect on the acute and late phase of HD induced ocular lesions in rabbit eyes. The effect of treatment with αPI in this study was not conclusive. However, when given in addition to DOX or IL it prevented the amelioration found in the DOX or IL groups.Since steroid treatment (Dexamycin® Ophthalmic solution) during the acute phase period had a larger beneficial effect than the tested MMP inhibitors, but a comparable effect on the late phase lesion, we suggest testing the combined effects of steroids and MMPI in a follow up study.

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