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K. G. Sheets, M. K. Ertel, Y. Zhou, W. C. Gordon, P. Gjorstrup, N. G. Bazan; Cell Specific Targeting by NPD1 Induces Resolution of CNV Injury. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6185.
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AMD is a chronic inflammatory process. Failure to resolve this inflammation ultimately results in choroidal neovascularization (CNV) and rapid vision loss. We previously demonstrated that the anti-inflammatory and neuroprotective docosanoid, neuroprotectin D1 (NPD1), inhibits laser-induced CNV. Here, we asked if NPD1 altered the presence of inflammatory mediating cells.
Mice were given laser-induced CNV and treated with vehicle or NPD1. Choroid flatmounts were prepared at 7 and 14 days after CNV induction. Flatmounts were labeled with isolectin B4 (IB4), CD11b, and Hoechst, visualized by 3D confocal microscopy, and label volumes determined using NIH ImageJ software.
Morphological and immunofluorescent inspection revealed two populations of CD11b positive cells. Activated microglia were distinguished by double label of CD11b and IB4. The second CD11b positive population was extensively associated with vascular endothelial cells, having the appearance of perivascular cells. At 7d, total microglia volume was reduced 65% by NPD1 treatment, and 46% at 14d. Neither treatment nor time affected total perivascular cell volume. NPD1 reduced the vascular endothelial volume by 48% and 52% at 7 and 14d, respectively. At 7d post-laser, the microglia:endothelia ratio was reduced 42% by NPD1; there was no difference at 14d. NPD1 increased the perivascular:endothelia ratio 35% at 7d; at 14d, the ratio was greater than 2 fold higher.
NPD1 reduces the presence of activated microglia with a concomitant reduction in vascular endothelial cells, yet the ratio of microglia to endothelia remains similar throughout. Two possible explanations are that NPD1 reduces the inflammatory response or promotes resolution. Since the laser stimulus was equivalent in all retinas, it is assumed that the inflammatory response was also equivalent and, thus, we conclude that NPD1 promotes the resolution of the inflammatory process. Secondly, the ratio of perivascular cells to endothelia cells was higher in NPD1 treated mice. Since angiogenic sprouting is inhibited by normal association of perivascular cells (e.g., pericytes) with endothelial cells, we also conclude that the NPD1-triggerred increase in perivascular association acts to stabilize new vascular endothelial cells, resulting in reduced pathological angiogenesis.
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