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R. A. Sack, P. Iserovich, S. Sathe, A. Beaton, A. Leonardi, K. H. Gotlinger, L. Bellner, M. Dunn, M. laniado Schwartzman; Proteomics, Lipidomic & Angiogenesis- Normal & Allergic Tears. Invest. Ophthalmol. Vis. Sci. 2010;51(13):416.
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To determine the distribution of a wide range of inflammatory, immune and angiogenic modulators in tears from normals (N) and individuals with allergic and auto-immune diseases and to relate composition to functional activity.
Capillary tube collected tears from N and individuals with VKC/AKC, OCP and Rosacea with corneal involvement in the forms of ulceration, scarring and neovascularization were probed for >60 low abundance proteins using membrane arrays and microwell-based arrays employing a lab-developed protocol obtaining sensitivities in some instances down to the fg/ml range. Selected samples were subject to LC/MS lipidomic analysis and assayed for the capacity to induce endothelial cells in culture to undergo pseudo-capillary tube formation.
Array analysis revealed that N tears contained ng to subng/ml quantities of numerous angiogenic modulators including ANG, VEGF, EGF, IP10, GROα, VEGF-R2 and IL8 but exhibited on bioassay negligible net angiogenic activity. Pathological samples most often contained markedly elevated levels of many of these proteins, cytokines (including IL1a, b, 5, 6, 8, 10, 13, 17, 23,TNFα, β and INFγ), growth factors, soluble receptors, PMN cells, eosinophils and activated Th2-specific chemokines. The latter included specific biomarkers eotaxin and TARC (4:N to 285 pg/ml-VKC/AKC) with these changes most pronounced in the VKC/AKC and OCP samples. Interestingly, these samples displayed selective increases in VEGF-R1 (N:234 to 2977 pg/ml-VKC/AKC) and TNFα-RII (5 - 234 pg/ml) while the concentration of VEGF-R2 which was very high, remained relatively static. LC/MS analysis revealed several mitogenic and angiogenic eicosanoids including HETE and HETrE metabolites that were absent in N tears. On bioassay some pathological samples exhibited a net angiogenic activity.
N tears exhibit negligible net angiogenic stimulatory capacity in part due to high levels of IP10, VEGF-R2 and possibly paradoxically GROα (see Cao..Folkman,1995). The distribution of bioactive proteins and lipids in tears is dramatically altered in allergic and autoimmune diseases in a manner consistent with IL17, Th2 and eosinophil involvement with TARC and eotaxin evident. This results in a shift in angiogenic balance perhaps contributing to the risk of neovascularization. VEGF-R2 and TNFα-RII may play a role in protecting the cornea in allergic conditions. Arrays can be of diagnostic value.
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