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The matrix metalloproteinase inhibitor SM 1489 reduces MMP-9 activity after sulfur mustard exposure <i>in vivo</i>

TitleThe matrix metalloproteinase inhibitor SM 1489 reduces MMP-9 activity after sulfur mustard exposure in vivo
Publication TypeConference Proceedings
Year of Conference2005
AuthorsGerecke D.R., Bhatt P., Chang Y., Sabourin C.L., Rudge, Jr T.L., Kiser R.C., Casbohm S.L., Gordon M.K., Riley D.J., Shakarjian M.P., Casillas R.P.
Conference NameProceedings of the 44th Annual Meeting of the Society of Toxicology
Conference LocationNew Orleans, LA
KeywordsSulfur Mustard

Bis(2-chloroethyl)sulfide (sulfur mustard, SM) is a chemical warfare agent that penetrates the skin rapidly, causing extensive blistering within several hours. The damage includes separation of the dermis from the epidermis, potentially as a result of collagen degradation in the basement membrane zone by matrix metalloproteinases (MMPs). We hypothesize that skin damage is increased by upregulation of the MMPs following mustard-induced inflammation. MMP-2 (gelatinase A) and MMP-9 (gelatinase B) in the absence or presence of MMP inhibitors were investigated to better assess their role in SM-induced skin injury. Mouse ears were treated with 80 ìg of liquid SM and ear specimens collected 24, 72, and 168 hours after exposure. Specimens were examined for the expression of MMP-2 and MMP-9 by histology, real-time PCR, gelatinase activity assays, and Western blot analysis. SM exposure increased mRNA levels for MMP-9 by 2-fold, 8-fold, and 21-fold for 24, 72, and 168 hours, respectively, when compared to the control untreated ears. There were no observable changes in the MMP-2 mRNA levels between treated and controls. A time-related increase in overall gelatinase activity was observed in SM treated ears. Western blot analysis confirmed the increased gelatinase acivity was due to MMP-9. Pretreatment with the MMP inhibitor GM 1489 N-[(2R)-2-4-methylpentanoyl]-L-tryptophan-(S)-methyl-benzylamide resulted in a 50% reduction of MMP-9 mRNA at 72 and 168 hours after SM treatment when compared to samples without pretreatment with MMP inhibitor. These studies demonstrate that the MMP inhibitor GM 1489 is a promising candidate as an effective pharmacological countermeasure against SM injury. *This work is supported by the US Army Medical Research and Materiel Command under Contract No. DAMD17-02-C-0091

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