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T. Ecoiffier, S. Rashid, J. El Annan, R. Dana; Role of Alpha-4 Beta-1 Integrin (VLA-4) in Dry Eye Syndrome. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2308.
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Dry Eye Syndrome (DES) is a very common condition affecting more than 9 million Americans. Despite our current understanding that the etiology of DES is multifactorial, the precise contribution of the molecular factors that drive its immunopathogenesis, or that may serve as therapeutic targets, is yet to be determined.
Our approach was to inhibit the function of VLA-4 with topical application of a VLA-4 small-molecule antagonist, and to subsequently measure the clinical and molecular responses in a mouse model of dry eye. Dry eye was induced with use of the Controlled Environment Chamber (relative humidity = 25 ±5%, airflow = 15 l/min, temperature 21-23°C) combined with scopolamine administration (2mg per day) for 10 days. Corneas were assessed clinically for fluorescein staining on days 0, 2, 5, 7, and 10. The frequencies and distribution of CD11b+ monocytic cells in the cornea were determined by epifluorescence microscopy. Quantitative Real-Time PCR was performed on corneas to quantify the level of cytokine mRNA. Groups were compared statistically using the Mann-Whitney U test and 2-way ANOVA analysis.
Mice receiving VLA-4 antagonist demonstrated a significantly decreased level of corneal fluorescein staining score over the untreated control group (P < 0.0001). Additionally, VLA-4 antagonism was associated with a 12% overall decrease in the number of CD11b+ monocytes in the central cornea as well as a 24% decrease in TNF-alpha transcript. No significant difference was observed in IL-1 alpha levels.
Taken together, our data suggest that VLA-4 plays a role in promoting DES-associated inflammation by facilitating the migration of inflammatory cells, possibly via up regulating TNF-alpha levels in the cornea.
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