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DOI: 10.1055/s-2007-963760
© Georg Thieme Verlag KG Stuttgart · New York
Pathomechanismen der Alterung des RPE und prophylaktische Therapieoptionen im Hinblick auf die AMD
Pathomechanisms für Aging of Retinal Pigment Epithelium (RPE) and Prophylactic Therapy Options in Regard to AMDPublikationsverlauf
Eingegangen: 9.11.2007
Angenommen: 23.11.2007
Publikationsdatum:
02. Juni 2008 (online)

Zusammenfassung
Ein intaktes retinales Pigmentepithel (RPE) ist für die Funktion der darüber liegenden neurosensorischen Netzhaut eine zentrale Voraussetzung. In der postmitotischen einlagigen Zellschicht des RPE sind unterschiedlichste Funktionen, wie z. B. Abbau der Photorezeptoraußensegmente, Vitamin-A-Stoffwechsel, Unterstützung des retinalen Metabolismus und Aufrechterhaltung der äußeren Blut-Retina-Schranke vereinigt. Bedingt durch die Belastungen einer hohen Stoffwechselrate, hoher okularer Sauerstoffspiegel, Exposition mit energiereichem kurzwelligem Licht und einer damit verbundenen Bildung von freien Sauerstoffradikalen ist das RPE auf effektive Schutzsysteme angewiesen. Trotz hochdifferenzierter Abwehrmechanismen gegenüber diesem Stress kommt es im Rahmen der Alterung zu einem kumulativen Schaden im RPE, der letztlich als eine wesentliche Teilkomponente in der Pathogenese der altersabhängigen Makuladegeneration zu sehen ist. Das bessere Verständnis dieser Vorgänge wird zur Entwicklung neuer prophylaktischer Ansätze beitragen, die in einer ständig älter werdenden Gesellschaft dringend gebraucht werden.
Abstract
An intact retinal pigment epithelium (RPE) represents an essential condition for the visual process. This post-mitotic RPE monolayer combines different functions such as degradation of photoreceptor outer segments, vitamin A cycle, support of retinal metabolism and maintenance of the outer blood-retina barrier. As a consequence of excessive metabolism, high oxygen levels, exposition to light of short wave length and ensuing radical formation, the RPE is highly dependent on protective systems. In spite of differentiated defence mechanisms, aging processes cause cumulative RPE damage, representing a major component of age-related macular degeneration (AMD), the leading cause of irreversible severe vision loss in people over 50 years old. A better understanding of the underlying pathophysiology will help to develop new prophylactic options which is becoming more and more important with increasing life expectancy.
Schlüsselwörter
RPE - Lysosomen - AMD - Lipofuszin - Radikale
Key words
retinal pigment epithelium (RPE) - lysosomes - age-related macular degeneration (AMD) - lipofuscin - radicals
Literatur
- 1
Age-Related Eye Disease Study Research Group .
A randomized, placebo-controlled, clinical trial of high-dose supplementation with
vitamins C and E, beta carotene, and zinc for age-related macular degeneration and
vision loss: AREDS report no. 8.
Arch Ophthalmol.
2001;
119
1417-1436
MissingFormLabel
- 2
Alves-Rodrigues A, Shao A.
The science behind lutein.
Toxicol Lett.
2004;
150
57-83
MissingFormLabel
- 3
Anderson D H, Mullins R F, Hageman G S. et al .
A role for local inflammation in the formation of drusen in the aging eye.
Am J Ophthalmol.
2002;
134
411-431
MissingFormLabel
- 4
Barouch F C, Miller J W.
The role of inflammation and infection in age-related macular degeneration.
Int Ophthalmol Clin.
2007;
47
185-197
MissingFormLabel
- 5
Bazan N G.
Survival signaling in retinal pigment epithelial cells in response to oxidative stress:
significance in retinal degenerations.
Adv Exp Med Biol.
2006;
572
531-540
MissingFormLabel
- 6
Beatty S, Koh H, Phil M. et al .
The role of oxidative stress in the pathogenesis of age-related macular degeneration.
Surv Ophthalmol.
2000;
45
115-134
MissingFormLabel
- 7
Bergmann M, Schutt F, Holz F G. et al .
Inhibition of the ATP-driven proton pump in RPE lysosomes by the major lipofuscin
fluorophore A 2-E may contribute to the pathogenesis of age-related macular degeneration.
FASEB J.
2004;
18
562-564
MissingFormLabel
- 8
Birch E E, Castañeda Y S, Wheaton D H. et al .
Visual maturation of term infants fed long-chain polyunsaturated fatty acid-supplemented
or control formula for 12 mo.
Am J Clin Nutr.
2005;
81
871-879
MissingFormLabel
- 9
Bok D.
Evidence for an inflammatory process in age-related macular degeneration gains new
support.
Proc Natl Acad Sci U S A.
2005;
102
7053-7054
MissingFormLabel
- 10
Boulton M, Dayhaw-Barker P.
The role of the retinal pigment epithelium: topographical variation and ageing changes.
Eye.
2001;
15
384-389
MissingFormLabel
- 11
Cangemi F E.
TOZAL Study: an open case control study of an oral antioxidant and omega-3 supplement
for dry AMD.
BMC Ophthalmol.
2007;
26 (7)
3
MissingFormLabel
- 12
Chen Y, Houghton L A, Brenna J T. et al .
Docosahexaenoic acid modulates the interactions of the interphotoreceptor retinoid-binding
protein with 11-cis-retinal.
J Biol Chem.
1996;
271
20 507-20 515
MissingFormLabel
- 13
Choi J S, Kim D, Hong Y M. et al .
Inhibition of nNOS and COX-2 expression by lutein in acute retinal ischemia.
Nutrition.
2006;
22
668-671
MissingFormLabel
- 14
Chua B, Flood V, Rochtchina E. et al .
Dietary fatty acids and the 5-year incidence of age-related maculopathy.
Arch Ophthalmol.
2006;
124
981-986
MissingFormLabel
- 15
Coleman H, Chew E.
Nutritional supplementation in age-related macular degeneration.
Curr Opin Ophthalmol.
2007;
18
220-223
MissingFormLabel
- 16
Elner V M.
Retinal pigment epithelial acid lipase activity and lipoprotein receptors: effects
of dietary omega-3 fatty acids.
Trans Am Ophthalmol Soc.
2002;
100
301-338
MissingFormLabel
- 17
Esparza-Gordillo J, Soria J M, Buil A. et al .
Genetic and environmental factors influencing the human factor H plasma levels.
Immunogenetics.
2004;
56
77-82
MissingFormLabel
- 18
Evans J R.
Antioxidant vitamin and mineral supplements for slowing the progression of age-related
macular degeneration.
Cochrane Database Syst Rev.
2006;
2
CD000254
MissingFormLabel
- 19
Frank R N, Amin R H, Puklin J E.
Antioxidant enzymes in the macular retinal pigment epithelium of eyes with neovascular
age-related macular degeneration.
Am J Ophthalmol.
1999;
127
694-709
MissingFormLabel
- 20
Globus M Y, Busto R, Lin B. et al .
Detection of free radical activity during transient global ischemia and recirculation:
effects of intraischemic brain temperature modulation.
J Neurochem.
1995;
65
1250-1256
MissingFormLabel
- 21 Holz F G, Pauleikhoff D, Spaide R F. et al .Altersabhängige Makuladegeneration. Springer-Verlag 2004
MissingFormLabel
- 22
Holz F G, Schutt F, Kopitz J. et al .
Inhibition of lysosomal degradative functions in RPE cells by a retinoid component
of lipofuscin.
Invest Ophthalmol Vis Sci.
1999;
40
737-743
MissingFormLabel
- 23
Howes K A, Liu Y, Dunaief J L. et al .
Receptor for advanced glyciation end products and age-related macular degeneration.
Invest Ophthalmol Vis Sci.
2004;
45
3713-3720
MissingFormLabel
- 24
Hunt S.
Increased dietary intake of omega-3-PUFA reduces pathological retinal angiogenesis.
Ophthalmologe.
2007;
104
727-729
MissingFormLabel
- 25
Ishibashi T, Murata T, Hangai M. et al .
Advanced glycation end products in age-related macular degeneration.
Arch Ophthalmol.
1998;
116
1629-1632
MissingFormLabel
- 26
Jang Y P, Zhou J, Nakanishi K. et al .
Anthocyanins protect against A 2E photooxidation and membrane permeabilization in
retinal pigment epithelial cells.
Photochem Photobiol.
2005;
81
529-536
MissingFormLabel
- 27
Jin X H, Ohgami K, Shiratori K. et al .
Inhibitory effects of lutein on endotoxin-induced uveitis in Lewis rats.
Invest Ophthalmol Vis Sci.
2006;
47
2562-2568
MissingFormLabel
- 28
Johnson E J, Schaefer E J.
Potential role of dietary n-3 fatty acids in the prevention of dementia and macular
degeneration.
Am J Clin Nutr.
2006;
83
1494S-1498S
MissingFormLabel
- 29
Kaemmerer E, Schutt F, Krohne T U. et al .
Effects of lipid peroxidation-related protein modifications on RPE lysosomal functions
and POS phagocytosis.
Invest Ophthalmol Vis Sci.
2007;
48
1342-1347
MissingFormLabel
- 30
Kim S R, Nakanishi K, Itagaki Y. et al .
Photooxidation of A 2-PE, a photoreceptor outer segment fluorophore, and protection
by lutein and zeaxanthin.
Exp Eye Res.
2006;
82
828-839
MissingFormLabel
- 31
Kopitz J, Holz F G, Kaemmerer E. et al .
Lipids and lipid peroxidation products in the pathogenesis of age-related macular
degeneration.
Biochimie.
2004;
86
825-31
MissingFormLabel
- 32
Krajčovičová-Kudláčková M, Valachovičová M, Pauková V. et al .
Effects of diet and age on oxidative damage products in healthy subjects.
Physiol Res.
2007; [Epub ahead of print];
MissingFormLabel
- 33
Lamb L E, Simon J D.
A2E: a component of ocular lipofuscin.
Photochem Photobiol.
2004;
79
127-136
MissingFormLabel
- 34
Lee E H, Faulhaber D, Hanson K M. et al .
Dietary lutein reduces ultraviolet radiation-induced inflammation and immunosuppression.
J Invest Dermatol.
2004;
122
510-517
MissingFormLabel
- 35
Maeda A, Crabb J W, Palczewski K.
Microsomal glutathione S-transferase 1 in the retinal pigment epithelium: protection
against oxidative stress and a potential role in aging.
Biochemistry.
2005;
44
480-489
MissingFormLabel
- 36
Maitra I, Marcocci L, Droy-Lefaix M T. et al .
Peroxyl radical scavenging activity of Ginkgo biloba extract EGb 761.
Biochem Pharmacol.
1995;
49
1649-1655
MissingFormLabel
- 37
Milbury P E, Graf B, Curran-Celentano J M. et al .
Bilberry (Vaccinium myrtillus) anthocyanins modulate heme oxygenase-1 and glutathione
S-transferase-pi expression in ARPE-19 cells.
Invest Ophthalmol Vis Sci.
2007;
48
2343-2349
MissingFormLabel
- 38
Miyauchi O, Mizota A, Adachi-Usami E. et al .
Protective effect of docosahexaenoic acid against retinal ischemic injury: an electroretinographic
study.
Ophthalmic Res.
2001;
33
191-195
MissingFormLabel
- 39
Nolan J M, Stack J, O’Donovan O. et al .
Risk factors for age-related maculopathy are associated with a relative lack of macular
pigment.
Exp Eye Res.
2007;
84
61-74
MissingFormLabel
- 40
Ohta Y, Okubo T, Niwa T. et al .
Prolonged marginal ascorbic acid deficiency induces oxidative stress in retina of
guinea pigs.
Int J Vitam Nutr Res.
2002;
72
63-70
MissingFormLabel
- 41
Parisi V, Tedeschi M, Gallinaro G. et al .
CARMIS Study Group: Carotenoids and Antioxidants in Age-Related Maculopathy Italian
Study Multifocal Electroretinogram Modifications after 1 Year.
Ophthalmology.
2007; [Epub ahead of print];
MissingFormLabel
- 42
Rafi M M, Shafaie Y.
Dietary lutein modulates inducible nitric oxide synthase (iNOS) gene and protein expression
in mouse macrophage cells (RAW 264.7).
Mol Nutr Food Res.
2007;
51
333-340
MissingFormLabel
- 43
Ranchon I, Gorrand J M, Cluzel J. et al .
Functional protection of photoreceptors from light-induced damage by dimethylthiourea
and Ginkgo biloba extract.
Invest Ophthalmol Vis Sci.
1999;
40
1191-1199
MissingFormLabel
- 44
Richer S, Stiles W, Statkute L. et al .
Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation
in the intervention of atrophic age-related macular degeneration: the Veterans LAST
study (Lutein Antioxidant Supplementation Trial).
Optometry.
2004;
75
216-230
MissingFormLabel
- 45
Roh Y J, Moon C, Kim S Y. et al .
Glutathione depletion induces differential apoptosis in cells of mouse retina, in
vivo.
Neurosci Lett.
2007;
417
266-270
MissingFormLabel
- 46
Rotstein N P, Politi L E, German O L. et al .
Protective effect of docosahexaenoic acid on oxidative stress-induced apoptosis of
retina photoreceptors.
Invest Ophthalmol Vis Sci.
2003;
44
2252-2259
MissingFormLabel
- 47
SanGiovanni J P, Chew E Y.
The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of
the retina.
Prog Retin Eye Res.
2005;
24
87-138
MissingFormLabel
- 48
Scholl H P, Weber B H, Nöthen M M. et al .
Y402 H polymorphism in complement factor H and age-related macula degeneration (AMD).
Ophthalmologe.
2005;
102
1029-1035
MissingFormLabel
- 49
Schutt F, Bergmann M, Holz F G. et al .
Isolation of intact lysosomes from human RPE cells and effects of A 2-E on the integrity
of the lysosomal and other cellular membranes.
Graefes Arch Clin Exp Ophthalmol.
2002;
240
983-988
MissingFormLabel
- 50
Schutt F, Bergmann M, Holz F G. et al .
Proteins modified by malondialdehyde, 4-hydroxynonenal, or advanced glycation end
products in lipofuscin of human retinal pigment epithelium.
Invest Ophthalmol Vis Sci.
2003;
44
3663-3668
MissingFormLabel
- 51
Schutt F, Bergmann M, Holz F G. et al .
Accumulation of A 2-E in mitochondrial membranes of cultured RPE cells.
Graefes Arch Clin Exp Ophthalmol.
2007;
245
391-398
MissingFormLabel
- 52
Schutt F, Davies S, Kopitz J. et al .
Photodamage to human RPE cells by A 2-E, a retinoid component of lipofuscin.
Invest Ophthalmol Vis Sci.
2000;
41
2303-2308
MissingFormLabel
- 53
Schutt F, Ueberle B, Schnolzer M. et al .
Proteome analysis of lipofuscin in human retinal pigment epithelial cells.
FEBS Lett.
2002;
528
217-221
MissingFormLabel
- 54
Schutt F, Völcker H E, Dithmar S.
N-Acetylcystein verbessert die lysosomale Funktion und beschleunigt den Abbau von
Photorezeptoraußensegmenten in der RPE-Zellkultur.
Klin Monatsbl Augenheilkd.
2007;
224
580-584
MissingFormLabel
- 55
Shamsi F A, Chaudhry I A, Boulton M E. et al .
L-carnitine protects human retinal pigment epithelial cells from oxidative damage.
Curr Eye Res.
2007;
32
575-584
MissingFormLabel
- 56
Skerka C, Lauer N, Weinberger A A. et al .
Defective complement control of factor H (Y402 H) and FHL-1 in age-related macular
degeneration.
Mol Immunol.
2007;
44
3398-3406
MissingFormLabel
- 57
Sparrow J R, Cai B.
Blue light-induced apoptosis of A 2E-containing RPE: involvement of caspase-3 and
protection by Bcl-2.
Invest Ophthalmol Vis Sci.
2001;
42
1356-1362
MissingFormLabel
- 58
Stahl W.
Macular carotenoids: lutein and zeaxanthin.
Dev Ophthalmol.
2005;
38
70-88
MissingFormLabel
- 59
Strauss O.
The retinal pigment epithelium in visual function.
Physiol Rev.
2005;
85
845-881
MissingFormLabel
- 60
Sundelin S P, Nilsson S E.
Lipofuscin-formation in retinal pigment epithelial cells is reduced by antioxidants.
Free Radic Biol Med.
2001;
31
217-225
MissingFormLabel
- 61
Tanito M, Yoshida Y, Kaidzu S. et al .
Acceleration of age-related changes in the retina in alpha-tocopherol transfer protein
null mice fed a Vitamin E-deficient diet.
Invest Ophthalmol Vis Sci.
2007;
48
396-404
MissingFormLabel
- 62
Trieschmann M, Beatty S, Nolan J M. et al .
Changes in macular pigment optical density and serum concentrations of its constituent
carotenoids following supplemental lutein and zeaxanthin: the LUNA study.
Exp Eye Res.
2007;
84
718-728
MissingFormLabel
- 63
Leeuwen van R, Boekhoorn S, Vingerling J R. et al .
Dietary intake of antioxidants and risk of age-related macular degeneration.
JAMA.
2005;
294
3101-3107
MissingFormLabel
- 64
Wang H, Nair M G, Strasburg G M. et al .
Antioxidant and antiinflammatory activities of anthocyanins and their aglycon, cyanidin,
from tart cherries.
J Nat Prod.
1999;
62
294-296
MissingFormLabel
- 65
Whitehead A J, Mares J A, Danis R P.
Macular pigment: a review of current knowledge.
Arch Ophthalmol.
2006;
124
1038-1045
MissingFormLabel
- 66
Xie Z, Wu X, Gong Y. et al .
Intraperitoneal injection of Ginkgo biloba extract enhances antioxidation ability
of retina and protects photoreceptors after light-induced retinal damage in rats.
Curr Eye Res.
2007;
32
471-479
MissingFormLabel
- 67
Yavin E.
Versatile roles of docosahexaenoic acid in the prenatal brain: from pro- and anti-oxidant
features to regulation of gene expression.
Prostaglandins Leukot Essent Fatty Acids.
2006;
75
203-211
MissingFormLabel
- 68
Zhou J, Cai B, Jang Y P. et al .
Mechanisms for the induction of HNE- MDA- and AGE-adducts, RAGE and VEGF in retinal
pigment epithelial cells.
Exp Eye Res.
2005;
80
567-580
MissingFormLabel
- 69
Zhou J, Jang Y P, Kim S R. et al .
Complement activation by photooxidation products of A 2E, a lipofuscin constituent
of the retinal pigment epithelium.
Proc Natl Acad Sci U S A.
2006;
103
16 182-16 187
MissingFormLabel
Prof. Dr. Florian Schütt
Universitäts-Augenklinik Heidelberg
INF 400
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