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Neera Tewari-Singh, Dinesh Goswami, Rama Kant, David A Ammar, J. Mark Petrash, Rajesh Agarwal; Changes in metabolome for identifying pathways involved in arsenical vesicating agent-induced corneal injury. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2277. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Lewisite [dichloro(2-chlorovinyl)arsine; L; LEW], an arsenical vesicant, causes severe pain and rapid injury to the ocular tissue with the edema of eyelids, inflammation, massive corneal necrosis and blindness. Detailed pathogenesis of corneal injury and related mechanisms from LEW exposure, which could be helpful in developing effective targeted therapies are not available. The goal of this study was to delineate changes in the metabolome, resulting from molecular perturbations at the genomic and proteomic levels, which could be useful to delineate new information on pathways and processes involved in vesicating agent response.
New Zealand white rabbit cornea [n=3-6, control rabbit cornea (left eye) versus those exposed to LEW (right eye) at 0.2 mg/L vapor for 2.5 or 7.5 minutes and then collected at 3, 7 or 14 days post LEW exposure] samples were prepared using the automated MicroLab STAR® system, and proteins precipitated to recover the chemically diverse metabolites. Metabolomic analysis was carried out by reverse phase UPLC-MS/MS and gas chromatography (GC)-MS. The data obtained was analyzed using Metabolon’s software.
Principal Component Analysis of biochemical profiles showed significant LEW exposure-based separation amongst the samples, mainly at day 3 or 7 post-exposure at 7.5 min. Analysis indicated that LEW exposure altered the intensity of metabolites related to: a) inflammatory and immune response [most evident changes in histamine, kynurenine and itaconate (2-3-fold)], b) oxidative stress (mainly related to glutathione catabolism, and altered levels of ascorbate and N-acetylcarnosine), c) lipid metabolism (an increase in phospholipids, plasmalogens, monoacylglycerols, and sphingolipids) and d) energetics and nucleotide metabolism (mainly in glycolytic intermediates at day 1 post-exposure).
The study outcomes here provide very essential and novel information on metabolite changes following LEW-induced corneal injury that could assist in delineating the complex chain of molecular events linking the LEW exposure with the observed ocular injuries/toxic outcomes and assist to develop more effective targeted therapies.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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