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Hiroki Kawano, Takashi Ito, Ikuro Maruyama, Taiji Sakamoto; The role of extracellular histones in retinal detachment. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2477.
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Histones are DNA-binding proteins and are involved in chromatin remodeling and regulation of gene expression. Histones can be released from dying cell and extracellular histones cause cellular damage and organ dysfunction during sepsis, sterile inflammatory liver injury, and acute kidney injury. Regardless of these clinical significances, its role and relevance to ocular diseases have been mostly unknown. The purpose of this study was to investigate the role of histone on retinal cells and their pathology focusing on retinal detachment (RD).
The oxidative stress was introduced with H2O2 in cultured rat retinal progenitor cells R28 and the expression of histone H3 was evaluated by Western blot. RD model was produced by subretinal injection of hyaluronan in rats and the expression of H3 was examined by immunohistochemistry. In addition, we assessed the vitreous concentrations of histone H3 by enzyme-linked immune-sorbent assay and their relationships with cytokine levels a using cytometric bead array in human eyes with various ocular pathologies. Furthermore, the cytokine profile analysis and cell viability assay were performed to show the toxicity of histones to human retinal pigment epithelial (RPE) cell line, ARPE-19 using WST-1 assay.
Oxidative stress induced the release of histone H3 from retinal R28 cells. In rat eyes, histone H3 was observed in the outer side of detached retina associating with photoreceptor necrosis but not apoptosis. Furthermore, the vitreous levels of histone H3 in patients with RD (30.9 ng/ml) were significantly higher than those of macular hole or epiretinal membrane (less than detection level, P<0.05). However, they were not correlated with IL-6 or IL-8 levels. In ARPE-19 cells, histones induced IL-8 secretion (2.5 times of control. P<0.05). However, cell death was also induced at higher doses.
Our results indicate that histones are released from damaged retinal in RD. This may deteriorate the condition of retinal microenvironment by inducing inflammation and cell death in RPE cells.
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