Chloroquine causes lysosomal dysfunction in neural retina and RPE: implications for retinopathy.
Chronic use of chloroquine has been shown to induce numerous pathophysiological defects in the retina. This drug has the ability to alter pH of intracellular compartments and lysosomal function of the retinal pigment epithelium (RPE) and retinal neurons may constitute the basis of chloroquine retinopathy. The aim of the current study was to investigate pathogenic alterations in retinal cells continuously exposed to chloroquine using appropriate in vivo and in vitro models. Male hooded Lister rats were implanted with osmotic mini pumps which released chloroquine continuously over a period of seven days. The eyes were processed for electron microscopy and ultrastructural abnormalities determined in the neural retina and quantified using stereology in the retinal pigment epithelium (RPE). RPE were also exposed to chloroquine in vitro and lysosomal pH changes were investigated using a pH sensitive probe. Degradative capacity was also analysed using FITC labeled rod outer segments (ROS). Chloroquine-treated animals displayed several ultrastructural abnormalities including numerous membranous cytoplasmic bodies (MCBs) in retinal neurons. Cone photoreceptors displayed numerous MCBs although rods did not. The RPE of the treated groups all showed significantly higher numbers of lysosomal associated organelles (LAO) than the control group (p < 0.001). The in vitro experiments demonstrated chloroquine-mediated rises in lysosomal pH and an increase in lysosome/phagosome accumulation of ROS in the chloroquine treated group (p < 0.01). The current study demonstrates that chloroquine disrupts lysosomal function in retinal neurons and RPE. The evidence presented provides a clear pathogenic basis for the functional defects experienced by patients with chloroquine retinopathy.
Mahon
G J
GJ
Eye Department, Institute of Clinical Science, Royal Victoria Hospital, Belfast, N. Ireland. g.mahon@qub.ac.uk
Anderson
H R
HR
Gardiner
T A
TA
McFarlane
S
S
Archer
D B
DB
Stitt
A W
AW
D000818:Animals; D018501:Antirheumatic Agents / Q000633:toxicity*; D018929:Cell Culture Techniques; D002738:Chloroquine / Q000633:toxicity*; D003594:Cytoplasmic Granules / Q000378:metabolism; D004343:Drug Implants; D006863:Hydrogen-Ion Concentration; D015918:Infusion Pumps, Implantable; D008062:Lipofuscin / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D010587:Phagocytosis / Q000502:physiology; D010588:Phagosomes / Q000187:drug effects; D010857:Pigment Epithelium of Eye / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D012164:Retinal Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D012374:Rod Cell Outer Segment / Q000378:metabolism
D018501:Antirheumatic Agents; D004343:Drug Implants; D008062:Lipofuscin; D002738:Chloroquine