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Akiko Okubo, Munefumi Sameshima, Kazuhiko Unoki, Fumiyuki Uehara, Alan C. Bird; Ultrastructural Changes Associated with Accumulation of Inclusion Bodies in Rat Retinal Pigment Epithelium. Invest. Ophthalmol. Vis. Sci. 2000;41(13):4305-4312.
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purpose. To determine the structural changes in the retinal pigment epithelium
(RPE) and neighboring structures induced by intravitreal injection of a
lysosomal protease inhibitor.
methods. Eleven-week-old Sprague–Dawley rats were injected with 5 μl of a
lysosomal protease inhibitor, E-64 (2.22 μM), intravitreally once and
killed at 24 hours, 48 hours, or 7 days later. Others received two or
three injections at 48-hour intervals or three daily injections, and
killed at 1, 4, and 7 days after the last injection. Eyes were
enucleated and retinal tissues were processed for light and electron
results. A single injection of E-64 caused only a transient accumulation of
phagosome-like and phagolysosome-like inclusion bodies in the RPE. By
contrast, repeated injection caused progressive accumulation of these
inclusions followed by altered RPE cell conformation, and changes in
organelles such as loss of smooth endoplasmic reticulum (SER). This was
accompanied by shortening and loss of photoreceptor outer segments
without prior dysmorphic changes, alteration of choroidal capillaries,
and invasion of Bruch’s membrane by fibroblasts and pericytes.
Intravitreal injection of vehicle as control induced no structural
conclusions. E-64 treatment induced structural changes in the outer retina. The
causal relationship between accumulation of inclusions in RPE and
changes in other subcellular organelles and neighboring cells systems
is not clear. However, there are possible explanations: physical
disturbance of organelles, particularly SER by inclusions; cellular
damage by consequent upon accumulation of A2-E; or, shortage of
recycled material due to reduced degradation of
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