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J. T. Rosenbaum, J. M. Kezic, S. R. Planck, H. L. Rosenzweig; A Comparison of the Ocular Inflammatory Response Induced by Local versus Systemic Lps Treatment. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4821.
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Several observations in the study of endotoxin-induced uveitis (EIU) indicate a differing ocular response following local versus systemic administration of LPS. TLR4 is activated by LPS and, in turn, can activate the MyD88 and TRIF intracellular signaling pathways. We sought to determine if there is a difference in the relative activation of the MyD88 and TRIF pathways in mouse eyes after systemic (i.p) versus local (intravitreal; ivt) LPS treatment.
Female BALB/c mice were administered 250 ng of ultrapure LPS intravitreally (local) or 100 µg i.p (systemic). Ocular inflammation was assessed at 4h, 6h and 24h post-LPS injection by intravital microscopy, which quantifies adherent, rolling and infiltrating cells in the iris, and by histological analysis. Cytokines of the MyD88 (IL-6, IFN-gamma, IL1-beta) and TRIF (RANTES, MCP-1) pathways were analyzed in dissected ocular tissues at 4h by Luminex assay.
Intravital microscopy revealed that whilst the numbers of rolling and adherent cells in the iris vessels were similar between treatment groups, locally administered LPS produced a much larger cellular infiltration of the iris tissue than mice treated with systemic LPS. Peak inflammation in ivt-treated eyes was at 6h, with only a minimal infiltrate in ip-treated eyes at 4h, 6h and 24h. Histological analysis confirmed intravital microscopy observations, with ivt LPS-treated eyes demonstrating typical features of anterior uveitis but only mild cellular infiltrate in eyes from i.p LPS-treated mice. Cytokine analysis of protein from ocular tissues at 4h revealed MCP-1 as more highly produced by iris and corneal tissue than by retina. IL-6 and RANTES were also highly secreted by iris tissue, whilst IFN-gamma and IL1-beta production was low. Surprisingly, systemically administered LPS produced higher levels of MCP-1, IL-6 and RANTES in the iris than locally administered LPS.
Although the administration of local LPS induced a larger cellular inflammatory response in the eye, systemically-administered LPS appears to produce a greater cytokine response in iris tissue. This is reflected in the high levels of MCP-1, IL-6 and RANTES produced at 4h post-systemic LPS. MCP-1 appears to be a prominent cytokine involved in the development of EIU.
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