SURVEY OF OPHTHALMOLOGY VOLUME 51 � NUMBER 5 � SEPTEMBER–OCTOBER 2006
MAJOR REVIEW
Photochemical Damage of the RetinaJiangmei Wu, MD, PhD, Stefan Seregard, MD, PhD, and Peep V. Algvere, MD, PhD
Department of Vitreoretinal Diseases, Saint Erik’s Eye Hospital and Karolinska Institutet, Stockholm, Sweden
Abstract. Visual perception occurs when radiation with a wavelength between 400 and 760 nmreaches the retina. The retina has evolved to capture photons efficiently and initiate visualtransduction. The retina, however, is vulnerable to damage by light, a vulnerability that has longbeen recognized. Photochemical damage has been widely studied, because it can cause retinal damagewithin the intensity range of natural light. Photochemical lesions are primarily located in the outerlayers at the central region of the retina. Two classes of photochemical damage have been recognized:Class I damage, which is characterized by the rhodopsin action spectrum, is believed to be mediated byvisual pigments, with the primary lesions located in the photoreceptors; whereas Class II damage isgenerally confined to the retinal pigment epithelium. The action spectrum peaks in the shortwavelength region, providing the basis for the concept of blue light hazard. Several factors can modifythe susceptibility of the retina to photochemical damage. Photochemical mechanisms, in particularmechanisms that arise from illumination with blue light, are responsible for solar retinitis and foriatrogenic retinal insult from ophthalmological instruments. Further, blue light may play a role in thepathogenesis of age-related macular degeneration. Laboratory studies have suggested that photo-chemical damage includes oxidative events. Retinal cells die by apoptosis in response to photic injury,and the process of cell death is operated by diverse damaging mechanisms. Modern molecular biologytechniques help to study in-depth the basic mechanism of photochemical damage of the retina and todevelop strategies of neuroprotection. (Surv Ophthalmol 51:461--481, 2006. � 2006 Elsevier Inc. Allrights reserved.)
Key words. age-related macular degeneration � blue light � chromophore � light exposure �optical radiation � photochemical damage � photo-oxidation � photoreceptor � retina �retinal pigment epithelium
I. The Retina
The retina is the innermost layer of the eyeball andit is made up of cells with vastly different functions.The outer monolayer is known as the retinalpigment epithelium (RPE), and inside of this isthe inner neurosensory retina, which consists ofphotoreceptor cells, bipolar cells, ganglion cells,horizontal cells, amacrine cells, and interplexiformcells. The neurosensory retina also contains glialelements. Not only are the cells of the retina highlyspecialized, different areas of the retina, such as the
46
� 2006 by Elsevier Inc.All rights reserved.
macular and peripheral areas in primate species, arealso highly specialized.
Two classes of photoreceptor cells, rods andcones, are present in the retina. These cells initiatethe visual process in the retina by converting theimage of the physical world generated by thedioptric media of the eye into neural signals.222
Cones are highly concentrated in the centre of theretina. These cells operate over a broad range oflight intensities between 10�1 and 105 lux, mediat-ing a photopic vision that is rich in color and
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462 Surv Ophthalmol 51 (5) September--October 2006 WU ET AL
characterized by high temporal and spatial resolu-tion. Rods, in contrast, are present across the retinaexcept for the very central region (known as thefoveola), and provide a scotopic vision up to 10�2 luxwith comparatively low resolution and high sensitiv-ity, but lacking in color information. Vision in thetransitional stage between 10�2 and 10�1 lux isknown as mesopic vision.162
Rods and cones are elongated cells that consist ofan outer segment, an inner segment, the perikaryon,the axon, and the synaptic terminal. The inner partof the photoreceptor is specialized for intercellularsignalling and for relaying the message to the brain,and the outer segment carries out photon captureand transduction. The outer segment consists ofa dense stack of disk-shaped double membranes inwhich the visual pigments, the photosensors, arelocated. The visual pigment in the rod is rhodopsin,which consists of opsin and the vitamin A aldehyde,11-cis-retinal. Phototransduction is triggered by thephotic conversion of 11-cis-retinal to all-trans-retinalin rhodopsin. The activation of rhodopsin startsa cascade of events that leads to the closure of sodiumchannels, hyperpolarization of the photoreceptormembrane and a decrease in the concentration ofintracellular calcium.207 The phototransduction sys-tem can be modulated by several proteins (such asS-modulin [recoverin], S-antigen [arrestin], guany-late cyclase-activating protein, phosducin, and cal-modulin) in a calcium-dependent manner, and thesemodulations induce light and dark adaptation.67
Rhodopsin is regenerated in the RPE through thevisual cycle of retinoid metabolism.25,220
Rods and cones, however, appear to expend mostof their energy not on the initiation of visualmessages, but on the incessant turnover of theirown molecules, a process that appears to be largelyindependent of function.299 In addition to molec-ular replacement, the outer segment itself iscontinuously turned over by membrane replace-ment.299 The concept of renewal implies theexistence of a steady state, in which the rate offormation equals the rate of destruction. Migrationof discs from the base to the tip of the outersegment of the rod takes approximately 10 days inprimate retinas.20,300 The periodic shedding of thediscs requires a highly effective process of degrada-tion. This requirement is met in the vertebrate eyewith the photoreceptive elements being located onthe retina’s outer surface adjacent to the RPE. Thismeans that the light that forms the image must passthrough all the layers of the neurosensory retinabefore reaching the outer segments. An efficientphagocytotic relationship between the tips of theouter segments and the RPE has thus beenestablished during evolution.7,134
In ontogenetic terms photoreceptor cells are post-mitotic, and can survive and function for the fulllifetime of the animal, as can all cells of the centralnervous system (CNS). Photoreceptors, however, aremore fragile than other CNS neurons, being morevulnerable to small mutations in their proteins andmore sensitive to environmental damage.135 Thefunction and the maintenance of the outer segmentrequire prodigious amounts of energy in the form ofphosphorylated nucleotides, particularly adenosinetriphosphate (ATP). The cells generate ATP princi-pally from glucose, both by oxidative metabolismand by glycolysis.290 This very intense oxidativemetabolism of glucose takes place in the cluster ofmitochondria in the ellipsoid portion of the innersegment. Photoreceptor cells use 3--4 times moreoxygen than other retinal and CNS neurons, andare probably the cells of the body with the highestrate of oxidative metabolism.4,149
Neurons in the inner half of the retina aresupplied by a well-developed retinal circulation,while blood vessels are strictly excluded from theouter half of the retina, by a process that is stillunknown. Glucose and oxygen reach the photore-ceptor cells by diffusion from the choroidal circu-lation across Bruch’s membrane and the RPE.3,6
The choriocapillaris is the most permeable capillar-ies in the body.19 Blood flow is so fast through thechoroid that the choriocapillaris bathes the outeraspect of the retina with near-arterial levels ofnutrients, fuelling in this way its vast metabolism.17
However, the choroidal circulation cannot regulateitself.18 One consequence of this is that when theoxygen consumption of photoreceptor cells falls,oxygen tension in the outer segment risessharply.46,148,292
RPE cells are polarized epithelial cells. Longmicrovilli interdigitate on their apical surfaces withthe outer segments of photoreceptor cells, whereastheir basal surfaces, which are formed with manyinfoldnings, are adjacent to Bruch’s membrane. Thetight junctions between RPE cells constitute theouter blood retinal barrier, blocking the passage ofwater and ions. The RPE plays a critical role in thecontrol of the volume and the composition of thefluid in the subretinal space through the activetransport of ions, fluid, and metabolites, and thiscontrol is in turn responsible for maintaining theintegrity of the RPE-photoreceptor interface.76 RPEcells play a role in the phagocytosis of photorecep-tor outer segment tips,24 and they play a major rolein the regeneration of visual pigments.25,220 Further,the presence of intracellular melanin granules andmany microperoxisomes, and the presence ofantioxidative enzymes, suggest that the RPE is activein detoxification.24 The RPE has no photoreceptive
PHOTOCHEMICAL DAMAGE OF THE RETINA 463
or neural function, but it is essential to the supportand viability of photoreceptor cells.243
Circadian clock regulation of the visual systemranges from a spontaneous rhythm in the synthesis ofmelatonin and in the shedding of discs in somespecies, to subtle rhythmic regulation of responsive-ness to light and dark signals in other species.36 Theretina is the only tissue in mammals that regulatesphotoreception, both visual and nonvisual.103 Non-visual photoresponse encompasses several responsesto light, including circadian entrainment, melatoninsynthesis, and pupillary light responses.74,152--154,263
These nonvisual irradiance detection tasks takeplace through a melanopsin-associated photosensi-tive system.16,102,200,219 and through vitamin B2-basedblue-light photoreceptors.175,225,255
II. Optical Radiation and The Eye
A. THE ELECTROMAGNETIC SPECTRUM
The term electromagnetic radiation covers radiofrequency, microwave, infrared, visible (light), ultra-violet, x-rays, and gamma radiation, all of which arepropagated both in free space and in matter. Theseradiations together form the electromagnetic spec-trum, although no upper or lower limit to thespectrum has been defined. Any source of radiationemits electromagnetic radiation that has a character-istic energy associated with each photon, and thephoton energy increases with increasing frequency.Ultraviolet radiation (UVR, with a wavelength of100--400 nm), visible radiation (visible light; 400--760 nm), and infrared radiation (IR, 760--10,000nm) are known as optical radiation. Several sub-bandswithin the optical radiation region have beendefined based on the similarity in photon energy,tissue penetration, and general aspects of thebiological effects, where UVR has been subdividedinto UVC (100--260 nm), UVB (260--315 nm), andUVA (315--400 nm), and IR has been subdividedinto IRA (700--1,400 nm), IRB (1,400--3,000 nm),and IRC (3,000--10,000þ nm). Visible light isreferred to as short- (blue), medium- (green), andlong-wavelength (red) radiation.232
B. PROPAGATION AND ABSORPTION OF OPTICAL
RADIATION IN THE EYE
The way in which light penetrates tissue is animportant factor in determining the type of photo-biological effects produced. Absorption and scatter-ing of the light by the tissue depends on thewavelength of the light, and these processes in turngovern light propagation.104,112 The optical proper-ties of the ocular media play an important role indetermining the exposure of the retina. The cornea
absorbs essentially all UVR below 295 nm, whereasthe lens absorbs most of the near UVB (300--315nm) and essentially all UVA. However, the trans-mittance of the cornea and that of the lens changeswith age. More short wavelength radiation reachesthe retina in the young eye than in the aged eye.Nevertheless, the ocular media (cornea, aqueoushumor, lens, and vitreous body) of the normal eyetransmit at least 1% of the radiation over the entirerange from 400--1,400 nm, which is known as theretinal hazard region. Water absorbs radiation ofwavelengths greater than 1,400 nm very heavily,and essentially all incident radiation is absorbed bythe cornea (Barker F, Brainard G: The directspectral transmittance of excised human lens asa function of age. US Food and Drug Administra-tion Report, 1991).23
The eye focuses incoming light rays to formimages on the retina. The focussing processconcentrates the light, increasing the power densityof light on the retina. Thus, light that deliversa radiant exposure insufficient to produce skindamage may cause eye injury when focused onto theretina. Several other factors must be taken intoaccount when considering how much radiationreaches the retina. These factors include the di-rection of gaze, the diameter of the pupil, whetherthe pupil is obscured by the lids, and whether thesubject has responded with an aversion reflex.230,231
Reflection and light scattering in the retinal layersand choroidal layers are not important whenassessing the impact of radiation on the retina,because the fraction that is diverted from the retinain this way is small compared with the directirradiation.79 The property of absorption of theretina thus predominantly determines the photobi-ological effects on it, as summarized in Sections VI.Aand V.C below. The portion of a molecule, orfunctional group, that absorbs an incident photon isknown as a chromophore or photosensitizer.
C. QUANTITIES AND UNITS
Two systems of terms and units are used toquantify optical radiation.170 One is a physicalsystem called the radiometric system, which isconcerned only with the energy content of theradiation. The other system, known as the photometricsystem, describes optical radiation in terms of itsability to elicit the sensation of light by the eye. Thephotometric system is thus limited to describinglight with wavelengths from approximately 400--760nm. The photometric system of units has the actionspectrum for both photopic vision and scotopicvision built into it.
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Table 1 compares two units that are commonlyused. Unfortunately, because the spectral distribu-tions of different light sources differ widely, there isno simple conversion factor between photometric(either photopic or scotopic) and radiometricquantities.
III. The Nature of Light Damagein the Retina
Light is necessary for vision but it can damage thesight organ itself—a property that has long beenrecognized. Light energy must be absorbed in orderto cause pathological changes. The portion ofenergy absorbed in any tissue depends on thetransparency of the tissue for the incident light.The transparency depends on the wavelengthcomponents of the light. At least three types ofradiation insult arise from radiation in the spectralrange 400--1400 nm, though the observable effectsactually form a continuum.
A. PHOTOMECHANICAL DAMAGE
Mechanical disruption arises mainly from therapid input of energy into the melanosomes of theRPE, which generates sonic transients, or shockwaves. These cause irreparable damage to photore-ceptors and the RPE.43,84,95 Tissue damage canresult from compressive or tensile mechanicalforces, which lead to the formation of micro-cavitation bubbles that are lethal for the RPE andfor other cells.30,112 The rate of delivery and theamount of energy absorbed are the dominantfactors that determine the amount of damage, notthe wavelength of the light.155,163 The effect iscaused by high irradiances (in the range megawattsto terawatts per cm2) and short exposure times (inthe range nanoseconds to picoseconds), duringwhich energy is absorbed so rapidly by the melaningranules in the RPE that heat dissipation cannottake place. Histological and ultrastructural studieshave shown that low level damage is limited to thevicinity of the melanosomes, particularly the outer
segment of the photoreceptor cells and the apicalportion of the RPE.95 The mechanical effect ofradiation from a YAG-laser is used therapeutically iniridotomy and capsulotomy. It is generally believedthat explosive vaporization, a rapid phase change oftissue water to steam, is the mechanism for RPEphotodisruption (Glickman RD, Jacques SL,Schwartz JA, et al: Photodisruption increases thefree radical reactivity of melanosomes isolated fromretinal pigment epithelium in Laser-tissue interac-tion VII. Proceedings of SPIE, Belingham, WA, 1996).
B. PHOTOTHERMAL DAMAGE
A quantum of radiant energy (a photon) can beabsorbed by a molecule only if the photon energyequals the energy difference between the molecule’scurrent energy level and an allowed higher energylevel. Vibrational and rotational quantum states ofmolecules predominate over excitation states for thelonger wavelengths in the visible spectrum and inthe near infrared (600--1400 nm).97 The vibrationenergy gained by the molecule is rapidly dissipatedthrough collisions with other molecules, momentar-ily raising the local level of mean kinetic energy,a process that is seen as a rise in temperature.Thermal lesions are not produced by the increasedkinetic energy until the irradiance of the radiation ishigh enough to raise the temperature by more than10�C above the ambient temperature in the retina.42
Consequently, thermal reactions have irradiancethresholds. Thermal effects generally arise fromexposure times ranging from microseconds to thetime required to reach thermal equilibrium (a fewseconds). However, the irradiance and the durationof exposure required to cause a certain level ofdamage are not inversely proportional. The amountof energy required to produce a certain thermaleffect increases for long exposure times, becauseheat dissipates during the exposure. The size ofthe image, in contrast, determines the magnitude ofthe temperature rise for a given irradiance andexposure time.42
TABLE 1
Common Radiometric and Photometric Terms and Units
Radiometric Definition Photometric
Radiant energy (J) Energy emitted Quantity of light (lm.s)Radiant power (W) Luminous flux (lm)Irradiance (W.m�2) Rate at which energy falls on or
passes through an area (dose rate)Illuminance (lm.m�2) or lux
Radiant intensity (W.sr�1) Luminous intensity (lm.sr�1or cd)Radiance (W.sr�1.m�2) The brightness of a source Luminance (cd.m�2)Radiant exposure (J.M�2) Term for dose in photobiology Light exposure (lx.s)
PHOTOCHEMICAL DAMAGE OF THE RETINA 465
Macromolecular systems are susceptible to ther-mal effects that disrupt their tertiary structure bybreaking hydrogen bonds and hydrophobic/hydro-philic bonds. The molecules are denatured, andabnormal molecular linkages may arise that lead topermanent loss of function. It has been suggestedthat the original site of energy absorption is themelanin pigment found in the melanosomes of theRPE and in the melanocytes of the choroids.158,163
Minimal thermal lesions show damage in the RPEand the photoreceptors. Thermal damage is greatestat the center of the lesion, where the temperaturerise is highest. Lesions caused by a high temperaturerise cover a greater area of the retina, since heatdiffuses away from the primary site of absorption.164
C. PHOTOCHEMICAL DAMAGE
A different form of interaction between radiantenergy and biological molecules takes place whenthe incident radiation has a wavelength in the high-energy portion of the visible spectrum: photochem-ical damage. An electron in an excited state canreturn to the ground state by dissipating the extraenergy in one of several ways. One way of dissipatingenergy is to split a bond in another molecule bydirect electron exchange or direct hydrogen ex-change, producing reactive oxygen species (ROS)such as singlet oxygen, superoxide radicals, hydro-gen peroxide, and hydroxyl radicals. The processmay also produce other free radicals.73,242,291
The formation of free radicals is more importantin producing tissue damage than the splitting ofbonds. Free radicals can attack many molecule typesand render them inactive.73,83,94,242 Tissues in whichthere is a large concentration of cell membranes areparticularly severely damaged because the attack offree radicals on the polyunsaturated fatty acids ina lipid induces a chain reaction of lipid peroxida-tion that breaks down membranous structures.73,209
Thus, photochemical damage spreads from theabsorbing molecule to other molecules in a chainreaction of uncontrolled, molecular disruption.
A particular wavelength of radiation always bringsabout the same type of change. A certain number ofphotons are needed to complete the reaction bybreaking a certain number of bonds, and thereaction proceeds at a rate determined by the rateat which photons arrive, the irradiance. There istheoretically a reciprocal relationship between theirradiance and the duration of exposure required tocause a certain level of damage, and photochemicalreactions depend on the total dose received. Thereciprocity rule breaks down at very long exposures(greater than 24 hours) because repair mechanismsbecome significant at such long exposure times. No
acute damage takes place below a certain thresholdirradiance level. Damage by chronic exposure, thatis, over periods of months or years, to high ambientlevels may be governed by different laws.143,241,301
IV. General Aspects of PhotochemicalRetinal Damage in Animals
It was as recently as 1965 that Noell accidentallydiscovered that the retina of albino rats can beirreversibly damaged by continuous exposure forseveral hours or days to environmental light withinthe intensity range of natural light. The intensity oflight that damages the retina is several orders ofmagnitude below the threshold of thermal injury inpigmented animals.181 The same damage as inalbinos of different strains is produced in pig-mented rats when the pupils are dilated.183 Manyinvestigators have subsequently characterized non-thermal retinal damage in several species, leading toa considerable volume of literature in the field.
A. A MORPHOLOGIC DESCRIPTION OF
PHOTOCHEMICAL RETINAL DAMAGE
Photochemical retinal damage occurs with a sev-eral different types of morphology. Kuwabara andO’Steen used light microscopy and electron micros-copy to study the pathological changes that occur inthe rat retina after exposure at room temperature tofluorescent light for several weeks or months.130,198
The first alterations occur in the outer segments ofthe photoreceptor cells. The outer segments appeartortuous and swollen, and the lamellar structuresbecome disrupted, showing separations and form-ing tubules and vesicles. Pyknosis and swelling ofmitochondria then take place in the inner seg-ments. The number of myeloid bodies in thepigment epithelium increases. Finally, all the dam-aged photoreceptors disappear, ending with com-plete adhesion of RPE and Muller cells. Moria et alhave given a similar description of the damage, witha similar time course of damage in the photorecep-tors.176 However, these authors found that the RPEis first disrupted in the region where the photore-ceptors are first irreparably damaged.
Rods are more sensitive than cones to lightdamage in the rat.41 Marshall et al studied pigeons,and they, in contrast, showed that the retinaldamage occurs exclusively to cones at exposures ofonly 6 hours at a light level corresponding to theluminance of an overcast sky. The damage to theouter segment lamellae is similar to the damage thattakes place in the rods of the rat.165 Lawwill exposedpigmented rabbits to light for up to four hours andshowed that damage is greatest in the area of the
466 Surv Ophthalmol 51 (5) September--October 2006 WU ET AL
visual streak, where the density of photoreceptors ishighest. The mild injury that occurs is disruption ofthe photoreceptors, while longer exposure timeresults in severe damage, with disappearance of bothphotoreceptors and the RPE.142
It is clear that the morphology of retinal lightdamage varies between species and that it dependson the severity of the damage. The inherentvariability of in vivo animal models, a broad spec-trum of experimental conditions, and a wide rangeof methods of evaluation make it difficult tocompare morphological characteristics of variouslight-induced retinal lesions. Typical photoreceptordamage takes place in monkeys exposed to daylightfluorescent lamps for periods of several hours,249
whereas the damage is restricted to the RPE whenmonkeys are exposed for 1,000 seconds to severalshort-wavelength spectral lines. The outer segmentsof photoreceptors first show signs of damage fivedays later when macrophages invade and the RPEcells are disrupted.98 It appears that retinal lightdamage is not a singular event that producesa singular set of abnormalities. Nevertheless, onegeneral characteristic of photochemical damage isthat it is greatest in the outer layers at the centralpart of the retina.
B. CLASSIFICATIONS OF PHOTOCHEMICAL
RETINAL DAMAGE
Several studies have attempted to determinewhich wavelengths of light produce the greatestlevel of damage. Noell et al used a series of narrow-band stimuli and showed that the 495-nm bandinduces more electroretinogram (ERG) loss thanthe 435-nm band and the 578-nm band, when theirradiance of all bands were equal. The authorsconcluded that the damaging effect of light iscorrelated to its efficiency of bleaching rhodop-sin.183 Retinal light damage is mediated by rhodop-sin in rats exposed to constant fluxes of photons atsix wavelengths.288 The hypothesis that light damageis mediated by photopigments is supported byexperiments in which monkey eyes were exposedto wavelengths that bleach predominantly thepigment in one particular class of photoreceptors.The results showed that light can selectively damageone class of cone receptor. The damage to the bluecones is permanent, whereas damage to the greencones is temporary.240,241
In contrast, Ham et al showed that retinalsensitivity depends on wavelength in a manner thatis unrelated to the absorption spectrum of rhodop-sin. The sensitivity of the monkey retina increasescontinuously with decreasing wavelength. The au-thors suggested that additional molecular systems
become vulnerable to electronic excitation andphotic damage as the energy per photon in-creases.97 Lawwill et al showed that the same is truefor rabbits by exposing them to lights of fourdifferent wavelengths.143 It appears that there aretwo different action spectra, one coinciding with theabsorption spectrum of rhodopsin; the other peak-ing in the short wavelength region (and provides thebasis for the concept of blue light hazard).
Subsequently, it has been proposed that there aretwo classes of photochemical damage of theretina.126,156 Class I damage has an action spectrumthat is identical to the absorption spectrum of thevisual pigment, and it appears after exposures ofseveral hours to weeks to relatively low irradiances,below 1 mW/cm2, of white light. The initial damageis mainly located in the photoreceptors. Class IIdamage has an action spectrum that peaks at shortwavelength, and this type of damage occurs underexposure to high irradiances of white light, above 10mW/cm2. The initial damage is generally confinedto the pigment epithelium. The two action spectraare found also for the rat retina, showing that thetwo classes of light damage, photoreceptor damage,and RPE-mediated damage, are present in differentanimal species.125,249,264,288
C. SUSCEPTIBILITY FACTORS IDENTIFIED IN
ANIMAL STUDIES
Several factors that enhance the susceptibility tolight damage have been identified in animal studies.So far, sex is not one of them.53,183,195
1. Wavelength
Two types of retinal light damage are induced inpigmented rats by irradiating small retinal patchesat either 380 nm or 470 nm.86 Exposure to light at380 nm specifically damages photoreceptor cells,particularly the rods. Exposure to light at 470 nmdamages both the photoreceptor layer and the RPE.Acute changes 1 hour after irradiation consistmainly of damaged mitochondria in these layers.The cells of the RPE later recover, and cells are lostfrom the photoreceptor layer. Interestingly, N-acetylcysteine, a potent antioxidant, protects therat retina from damage induced by light exposure at380 nm, but not at 470 nm.31 The types of spectraldamage are thus distinct in the early phases, despitethe remarkable similarity in the end effect of bothtypes of damage. Grimm et al have shown that bluelight causes severe retinal damage under experi-mental conditions in which green light induces nohistological changes in the retina.92 The spectraloutput of the light source is thus important for thephotochemical damage that occurs.
PHOTOCHEMICAL DAMAGE OF THE RETINA 467
2. Light Intensity and Exposure Duration
It has been believed that photochemical damagedepends on the total dose received. This impliesthat the light intensity and the duration required tocause a certain level of damage are correlated, anda longer light exposure can substitute for the use ofa lower intensity. Studies using the steady staterhodopsin level to measure retinal damage in ratsexposed to light of 20--160 lux showed that theluminance level and duration are reciprocally re-lated.213 The thickness of the outer nuclear layer(ONL) in rats exposed to light decreases almostlinearly as a function of cage illumination, in therange 133--950 lux.287 However, the reciprocityappears to hold for Class II damage,97,125,264 whileit does not hold for Class I damage, because repairprocesses affect the level of damage that is inflicted.Indeed, recovery from light-induced retinal damagehas been shown in a number of studies.97,129,130,
176,183,261 O’Steen et al have furthermore demon-strated that there are qualitative differences betweenthe damage from low intensity and that from highintensity.193,194,197 They showed that the rate ofdegeneration is directly related to the strength ofthe illumination and that the extent of retinaldegeneration and the involvement of the RPE isgreater with high intensity illuminants. They alsoshowed that the pattern of degeneration, especiallythe site of initial cell destruction, is different forhigh-intensity illumination. Evidence has recentlybeen presented showing that the transducin-de-pendent pathway is involved in retinal damage bylight with a low intensity. In contrast, retinal damageinduced by light with a high intensity does notdepend on transducin.101
3. Cumulative Effects of Light
Noell was the first to demonstrate the cumulativeeffect of light in retinal damage. He showed that a 5-minute exposure does not produce a significanteffect, whereas three and four exposures, each of 5minutes’ duration and each followed by a 1-hourdark interval, lead to significant damage. It is evenmore surprising that dose fractionation can producea more severe effect than the same total duration ofillumination without interruptions. However, thecumulative effect does not take place if the retinarecovers sufficiently from subliminal damage duringa dark interval before the next exposure isapplied.183 The cumulative nature of light damagehas been observed in several investigations.96,143,259
Griess and Blankenstein showed that the thresholdis related to the single-dose threshold through theadditivity, which in turn depends on the timebetween exposures.88 Organisciak et al have con-
firmed that intermittent light exposure can result ingreater photoreceptor damage than continuousexposure, and that it exacerbates type I damage inrats.189
4. Circadian Rhythm
Duncan and O’Steen showed that susceptibility tolight-induced cell death depends upon the periodduring the light--dark cycle at which animals receivea daily light exposure. They exposed rats to 4 hoursof high intensity fluorescent light during differentphases of the 14:10 hours light-dark cycle for 8consecutive days. The retinas of animals exposedduring the middle of the dark period or during thefirst 5 hours of the light period were significantlymore damaged than the retinas of animals exposedduring the last 9 hours of the light period.65
Increased exposure to light during the period ofrod outer segment phagocytosis enhances photore-ceptor damage.283 Organisciak et al exposed rats toa single dose of intense light at various times of theday or night, and showed that the loss ofphotoreceptors depends on the circadian cycle,being greatest when light exposure begins duringthe normal night-time phase of the diurnal cycle.The authors show that photoreceptor cell status atthe start of light exposure is a key factor indetermining the pathological effects of the light,and they suggest that the retina expresses anendogenous factor (or several factors) that en-hances or retards the process of cell death fromintense light.186 Interestingly, melatonin injectionsaffect the rate of disk shedding in rats282 andincrease the susceptibility to light damage,144,284
although melatonin is not simply a photosensitizerin the retina.
5. Adaptive State
Noell et al showed that retinal light damage iscorrelated with adaptive changes in photorecep-tors.179 They found that rats reared in darkness havean increased level of rhodopsin in the retina, andthat they are more susceptible to light-inducedretinal damage than animals reared in cyclic light.The rats become less susceptible to light damagewhen moved from a dark-rearing environment toone with weak cyclic light, whereas rats reared incyclic light become increasingly sensitive to lightdamage as they spend time in a dark environment.This observation was confirmed by Organisciak et al,who showed that 50% of photoreceptor cells indark-reared rats are lost after 8 hours of lightexposure. Approximately 24 hours are required toproduce the same degree of damage in rats rearedin cyclic light.191 Additional studies have shown that
468 Surv Ophthalmol 51 (5) September--October 2006 WU ET AL
rats reared under low illuminances have a higherrhodopsin-packing density, a greater mean outersegment length, and higher levels of docosahexae-noic acid (DHA; 22:6 n-3) than animals reared athigher light levels.10,190,204,205
Penn and Williams reared rats under differentlevels of environmental lighting and showed thatrhodopsin levels, mean rod outer segment length,and photoreceptor number vary inversely withincreasing rearing illuminance. However, there isno significant difference in the number of photonsabsorbed by the retina even when the lightilluminance differs by more than two orders ofmagnitude. This regulation of daily photon catchhas been attributed to adaptive changes in thephotoreceptor cells, a process known as photo-stasis.206 Moreover, animals reared in an 800-luxlight environment have higher levels of retinalglutathione-dependent antioxidative enzymes andvitamins E and C than animals reared under lowerlight levels.205 The retinas of these rats resist lightdamage, whereas the retinas of rats reared in a 5-lux environment loose nearly all photoreceptorcells. Thus, the photoreceptor cell can adaptmetabolically to its long-term light environment,and this adaptation influences the degree ofdamage that results from subsequent light expo-sure.
6. Photosensitizing Drugs
Certain substances are phototoxic for the eye.Exogenous agents that pass the blood--retina barriermay produce photochemical damage to the retina,if they absorb radiation in the near UV or visiblerange and have a cationic-amphiphilic nature.Heterocyclic, tricyclic, and porphyrin-related struc-tures are likely candidates for photosensitizers.216
Laboratory studies have shown that RPE cells arephotosensitized and cell death increases afterirradiation with blue light or UVR,34,169 whichexplains a pigment retinopathy in patients aftertreatment.
7. Aging
Susceptibility to light damage increases with agein a process that is distinct from age-relateddegenerative changes. The latter are concentratedto the periphery of the retina.273 O’Steen et alexposed animals of different age to the sameduration of light and compared the histology ofthe retina. Animals aged 3--5 weeks suffered nodamage; those aged 6--7 weeks showed minorstructural changes localized in the central retina;those aged 8 weeks had some photoreceptor de-struction in 80% of the circumference of the retina;
those aged 9--10 weeks showed discontinuities in theouter retinal layer, and these became progressivelymore severe in animals aged 11--14 weeks. Approx-imately 95% of the photoreceptors were damaged inadult retinas (16--24 weeks).195
8. Genetics
a. Ocular Pigmentation
Noell et al studied retinal damage in albino ratsand pigmented rats under identical illuminanceconditions and showed that the exposure time mustbe doubled in the pigmented rats to achieve thesame ERG loss, even when the pupils are dilated.183
However, monochromatic light focused onto theretina gives the same degree of damage inpigmented rats as in albinos. LaVail and Gorrinstudied experimental chimeras and translocationmice and showed that light-induced photoreceptorcell damage is independent of pigmentation phe-notype.137 Likewise, Lawwill showed that the levelsof damage throughout the retinas of rabbits aresimilar in the light pigmented and the darklypigmented patches of the RPE.142 Rapp et alexposed albinos and pigmented rats with dilatedpupils to light, where the light level was controlledto produce equal steady-state bleaching in the twostrains of rat. The retinal degeneration was similarin the two strains.212,213 Thus, ocular pigmentationdecreases retinal irradiance mainly by protectiveabsorption, and melanin itself does not mediatecellular damage.85
b. Species
There are genetic differences in the susceptibilityof animals to retinal light damage.27,138,196 The bestevidence for this comes from the studies by LaVailusing different strains of mice. The loss of the ONLafter 3 weeks of exposure varies between 20% and90%. The ONL loss is intermediate for exposureslasting up to 6 weeks in mice that result from a crossof the resistant strain (C57BL/6J-c2J) with thesensitive strain (BALB/cByJ).137,139 It has recentlybeen shown that the substitution of leucine bymethionine at position 450 of the protein RPE65correlates with a lower susceptibility to damage fromlight exposure in mice.53 Mice with the RPE65methionine variant have a lower age-related loss ofphotoreceptors, suggesting that this sequence vari-ation influences the effects of life-long lightexposure.279 However, the level of the RPE65protein is not strictly correlated with the rate ofrhodopsin regeneration, nor is it correlated with thesusceptibility to light damage in rats,109 although itis correlated in mice. This suggests that other
PHOTOCHEMICAL DAMAGE OF THE RETINA 469
genetic factors may also influence retinal sensitivityto light damage for different species.
c. Animal Models of Human Retinal Degeneration
Royal College of Surgeons rats (RCS rats) aregenetically predisposed to light-induced damage ofthe retina, and these rats are a well-characterizedmodel of autosomal recessive retinitis pigmentosa(RP) due to a defect in the RPE that results in anaccumulation of outer segment debris and a sub-sequent progressive loss of photoreceptor cells.63
The P23H and S334ter transgenic animal models ofRP have a lower phototoxicity threshold thannormal strains, and this supports the hypothesisthat patients with RP are more susceptible to visionloss when working in high-intensity light environ-ments.178,185,269
V. Photochemical Retinal Damagein Humans
A. SHORT-TERM AND LONG-TERM EXPOSURE
TO SUNLIGHT
Thousands of individuals suffered macular lesionsin one day in Germany in 1912, as a result of viewinga solar eclipse.298 Numerous cases of eclipseblindness have subsequently been reported. Eyesfrom patients who volunteered to stare at the sunprior to enucleation had various degrees of injury inthe RPE cells 38--48 hours later, whereas only mildtubulovesicular changes of the outer segments andmicrotubular aggregates had occurred in the innersegments of the photoreceptors. This explains thegood vision shortly after exposure. The damage tothe RPE resembles closely the damage that occurs inthe monkey 48 hours after exposure to blue light,Class II damage.98 The RPE regenerates rapidly, andthe integrity of the blood--retinal barrier is rapidlyrestored. The photoreceptors, however, begin todisappear and degenerate some time after theexposure.260 Some individuals may recover com-pletely from a given level of damage, whereas othersare left with permanent central scotomas. Experi-ments exploring the temperature increases requiredto cause thermal injury in the retina suggest thatthermal retinal injury thresholds for a retinal image158 mm in diameter are 10 times higher than theretinal irradiance that is experienced during directviewing of the sun.232 It is now believed that the bluelight damage mechanism alone is responsible forsolar retinitis.232
B. IATROGENIC EXPOSURE TO LIGHT
Numerous studies describe damage inflicted byophthalmic instruments, particularly the operating
microscope.54,157,167,171 Endoillumination duringvitrectomy is also a hazard.127,208 The conclusionsdrawn concerning damage in humans are sup-ported by experimental studies of monkeys exposedto the light of an operating microscope. Lesionswere produced mainly in photoreceptors and inRPE cells that resemble those seen in blue-lightinjuries.108 Moreover, photic maculopathy affec-ting photoreceptors and RPE cells has been in-duced by an indirect ophthalmoscope.258,262 Theseexperimental studies show that a chronic degener-ation takes place in the retina several months,indeed years, after photic injury, the symptoms ofwhich are macrophage invasion, impaired outersegment production, photoreceptor loss, RPE de-pigmentation, and proliferation and choroidalneovascularization.
C. IMPACT OF LIGHT EXPOSURE ON
AGE-RELATED MACULAR DEGENERATION
Age-related macular degeneration (AMD) is a de-generative disease that affects the photoreceptors,the RPE, Bruch’s membrane, and the choroid. It isthe predominating cause of legal blindness amongthose aged over 65.122,172 The clinical hallmark ofAMD is the appearance of localized deposits known asdrusen between the basement membrane of the RPEand Bruch’s membrane.78 Drusen are extracellularmasses of heterogeneous composition.45,113,159,177
The detailed mechanisms by which the drusen formare unknown. However, it has been suggested that theaccumulation of lipofuscin granules and otherphagocytic material in the RPE contributes to theformation and deposition of drusen.69,105,110,111
Damage to both rods and cones is limited by theconstant renewal of the disks.299 It is believed thatthe accumulation of incompletely degraded phag-osomes forms lipofuscin granules, which are man-ifested clinically as the age pigment.119,223 Onecomponent of lipofuscin, the orange-emitting pyr-idinium bisretinoid A2E, has been isolated andcharacterized.9,49,151,166,201,278 A2E is formed in rodouter segments by a sequence of reactions that isinitiated by the condensation of two molecules ofall-trans-retinaldehyde with phosphatidylethanol-amine. The accumulation of A2E in RPE cellsinterferes with lysosomal functions, inhibiting, forexample, protein and glycosaminoglycan catabolicpathways.106 Finnemann et al showed that A2E-loaded RPE degrades outer segment proteinsefficiently but cannot completely digest phospho-lipids, resulting in a build-up of undigested materialin the RPE.72
It has been suggested that the accumulation oflipofuscin in the RPE is partly related to light
470 Surv Ophthalmol 51 (5) September--October 2006 WU ET AL
exposure, and that the steep increase in lipofuscincontent during the first two decades of life may bedue to a high transmission of light through thelens, with a strong exposure to short-wavelengthvisible light and UVA.272 Interestingly, the rate ofaccumulation of lipofuscin in RPE cells is lower inblacks than in whites.274 The formation of A2E inthe photoreceptor outer segment membrane in-creases when rats are exposed to bright light.15 Anumber of studies have shown that the develop-ment of AMD is significantly correlated withexposure to sunlight.22,47,48,253,256 Long-term expo-sure to visible light particularly predisposes the eyeto AMD.253 The severe difficulty of assessinglifelong exposure to light in epidemiologicalstudies, however, prevents clear conclusions frombeing drawn, and the correlation remains contro-versial.1,107,124
Two hydroxyl-carotenoids (xanthophylls), luteinand zeaxanthin, are present in the primate retinaand are concentrated at the macula.12 The absor-bance spectrum of the macular pigment in situ hasa peak at 460 nm, and the pigment acts asa broadband filter.203,214 The macular pigmentmay protect the retina from blue light damage orit may act directly as an antioxidant.44,81,121,147 AMDis more prevalent in people who have light-coloredirides,106,246,275 whereas the optical density of themacula pigment is higher in people who have darkirides.99 Long-term dietary depletion of the maculapigment results in fundus hyperfluorescence relatedto the accumulation of high amounts of lipofuscinand drusen.160 Interestingly, the density of themacular pigment is inversely correlated with expo-sure to light.168
Individuals with nuclear opacity of the lens havea statistically significant reduced risk of developingdeteriorative changes in the macula.239,281 It isunclear whether cataract type is related to AMD,and studies have given inconsistent results.123,268
Furthermore, the incidence of AMD is significantlycorrelated with aphakia and pseudophakia.172,173,
265,267,268 The surgical trauma, and the increasedretinal exposure to the light from operating micro-scopes,35 may have detrimental effects. There isa dramatic change in the transmission of radiationthrough the eye when the lens is removed, becausethe lens absorbs the high-energy part of the visiblespectrum and UVA photons. Indeed, a loss of short-wavelength cones takes place in eyes with implantedlenses.280
Finally, the predilection of photic injury in theouter retina of the macular region further supportsthe hypothesis that cumulative exposure to in-tensive light is linked with the pathogenesis ofAMD.98,141,157,257,298
VI. Mechanisms of PhotochemicalRetinal Damage
A. CHROMOPHORES PROBABLY INVOLVED IN
THE INITIATION OF RETINAL DAMAGE
At least some light damage may be initiated by thevisual pigment in both rods and cones.87,183,241,288
Not only does the action spectrum of light damagecoincide with the absorption spectrum of rhodop-sin, the degree of retinal damage is also positivelycorrelated with the rhodopsin content in the retinabefore exposure to light.180,190 Photochemical dam-age is reduced when the visual cycle is inhibited byanesthetic halothane or 13-cis-retinoic acid andwhen the rate of rhodopsin regeneration has beenreduced by a nearly complete depletion of DHA33 orby the lack of protein RPE 65, which is involved inregeneration of 11-cis-retinal.91,118,228 Arrestin orrhodopsin kinase knock-out mice have an increasedsusceptibility to light damage, again suggesting thatthe light damage is mediated by rhodopsin,37,40
because transgenic mice lacking arrestin maintainprolonged activation of metarhodopsin II.297
There is, however, no evidence to support thehypothesis that rhodopsin itself is the photosensi-tiser that is responsible for photochemical damage.It seems likely that the formation of bleachedproducts of rhodopsin or other visual pigmentsleads to the formation of phototoxic molecules thatmediate retinal cytotoxicity. The activation ofrhodopsin and light-induced photoreceptor injuryhas been studied at a single-cell level.59 Light ofwavelength 470--490 nm induces the generation ofoxidants in both the inner segments and the outersegments of rods. Rhodopsin isomerization takesplace in the outer segments both during lighttransduction and during light-induced oxidativestress. Activated rhodopsin may mediate damagewithout requiring the activation of GTP-dependentor ATP-dependent phototransduction cascades.
Lipofuscin becomes apparent in the RPE cells ofhealthy retinas in humans by the age of 10.71
Lipofuscin contains several different fluorophoresthat are responsible for its characteristic broadbandfluorescence when excited with UV or blue light.66
Irradiation of lipofuscin with light of wavelength390--550 nm can generate superoxide anions, singletoxygen, hydrogen peroxide, and lipid hydroperox-ides,28,75,217,218 and the generation of these ROSincreases with decreasing wavelength.28,218 Thephototoxicity of lipofuscin compromises lysosomalintegrity; impairs the activities of catalase, superox-ide dismutase, and cathepsin D; and induces lipidperoxidation. These processes cause damage to themitochondrial DNA and damage to the RPEcells.55,226,271
PHOTOCHEMICAL DAMAGE OF THE RETINA 471
The retina harbors several other chromophoresthat may play a role in photochemical damage.Proteins that contain porphyrin, such as somemitochondrial enzymes, may be photoactive. Theporphyrin triplets that are formed by the absorptionof photons can result in the formation of singletoxygen and free radicals, and these may damage theprotein and other cellular constituents.26 Similarly,many enzyme systems contain flavins, such asriboflavin (vitamin B2), flavin mononucleotide(FMN), and flavin adenine dinucleotide (FAD).Photoexcited flavins can oxidise several amino acids,oxidize glucose, mediate photo-induced lipid per-oxidation, and induce protein crosslinking.77,227,229
In addition, it is generally believed that the majorfunction of melanin is to protect the photoreceptorsfrom scattered light. The biological role of melaninmay be related not only to its screening properties,but also to its antioxidant action.221 The number ofmelanosomes decreases with age, whereas thenumber of melanolysosomes and the concentrationof melanolipofuscin increase steadily with age.71
It is therefore natural to suggest that the initiationof damage occurring from discrete wavelengths oflight involves early distinct events. This process takesplace only if an array of chromophore candidatesexists in the retina. The trigger for light damagemay be located in the outer segment, the mitochon-drion, or another subcellular organelle. However,the molecular events that are involved in theinitiation of photochemical damage are largelyunknown.
B. THE ROLE OF PHOTOOXIDATION IN RETINAL
DAMAGE
The retina is particularly susceptible to oxidativedamage for a number of reasons: it has high oxygentension,5,29 its essential photosensitive functionmeans that it is exposed to large doses of radiation,it contains a high proportion of polyunsaturatedfatty acids in the photoreceptor outer seg-ments,11,245 and it contains numerous chromo-phores in the neuroretina and the RPE. Thephagocytosis of photoreceptor outer segments byRPE cells generates extracellular hydrogen perox-ide.252 Photochemical damage to the retina isa lifelong process, and it is essential that the retinais protected against the toxic ROS produced. Thisprotection in the retina, and in most other tissues, isprovided by enzymes such as superoxidase dismu-tase (SOD), catalase, heme oxygenase, severalisoforms of glutathione peroxidase and phospholi-pase, and by non-enzymatic antioxidants, such asvitamins E, A and C, melanin, lutein, and zeaxan-thin.13,100
The role of lipids and lipid peroxidation in lightdamage to the retinal and to RPE cells has beenstudied in particular detail.59,285 More than 60% ofthe fatty acids in the retina are polyunsaturated, themost abundant fatty acid is DHA.8,52,245 DHA levelsdecrease when rats are exposed to intense light andwhen they are reared in a high-light environ-ment,207,286 and it has been suggested that this fattyacid is involved in the process of retinal lightdamage. Light damage is significantly reduced or,indeed, prevented when retinal DHA is lowered orremoved by dietary manipulation.32,33,192 This ef-fect, however, may not only be the result ofa reduction in the rate of lipid peroxidation, butalso a reduction in the rhodopsin regeneration rate,which in turn result in a reduction in the sensitivityof the retina to light.
A number of studies using antioxidants supportthe hypothesis that oxidation results from intenselight exposure, and the oxidation precedes irre-versible photoreceptor death. The extent of pho-toreceptor loss is reduced when ascorbate issupplied by intraperitoneal injection.146,188,191 Theiron chelator desferrioxamine and the syntheticantioxidant dimethylthiourea (DMTU), a hydroxylradical trap, also protect from photoreceptor loss,and this implies that exposure to light initiates anoxidative process.131,145,187 Furthermore, the radio-protective dye WR-77913, which is a singlet oxygenquencher, prevents acute light-induced morpholog-ical changes in the tips of the outer segments.215
Phenyl-N-tert-butylnitrone, which is a spin-trappingagent, is incorporated into the retina after in-traperitoneal injection, and protects photoreceptorcells from the damaging effects of constant visiblelight.211 It is particularly interesting that treatmentwith ascorbate prevents the accumulation ofphagosomes in the RPE during light-induceddamage,21 and that this treatment is particularlyeffective in reducing damage in the RPE.182,184
Long-term dietary supplementation with zeaxan-thin reduces photoreceptor death in light-damagedJapanese quail.254
Other enzymes also play a role in protecting theretina from photo-oxidative damage. Heme oxygen-ase (HO) is the rate-limiting enzyme in hemedegradation and its expression is induced in manycell types by oxidative stress. HO 1 is induced in therat retina by exposure to intense green light, aneffect that is suppressed by DMTU.128 Mice carryinga mutated SOD I gene are more susceptible to light-induced retinal damage.174 Thioredoxin (TRX) isan endogenous redox regulator that protects cellsagainst several types of oxidative stress. The expres-sion of TRX is induced in the mouse retina after lightexposure.250 Intraocular injection of recombinant
472 Surv Ophthalmol 51 (5) September--October 2006 WU ET AL
TRX suppresses photo-oxidative stress.250 Mice withoverexpression of TRX are less susceptible to retinalphoto-oxidative damage.251
C. BLUE LIGHT--INDUCED RETINAL DAMAGE
Blue light presents an interesting paradox to theretina. On the one hand, it is essential for retinalphysiology, because it plays a role in nonvisualphotoreception and in controlling the circadianrhythm.60,103 On the other hand, it is the mosthazardous component of the visible spectrum,having the greatest potential for phototoxicity.97
Several molecules in the retina are implicated inmediating the phototoxicity of blue light.
Cytochrome oxidase absorbs blue light: theoxidized form has an absorption peak at about 420nm, whereas the reduced form has an absorptionpeak at about 440 nm.14 Exposure of isolated bovinepigment epithelium to blue light at 430 nm reducesthe transepithelial potential and induces morpho-logical changes in the mitochondria.202 The actionspectrum of the light that induces these changesclosely matches that of the mitochondrial enzymecytochrome oxidase c, and the spectra of otherhemoproteins. The expression of cytochrome oxi-dase in the retina and in the RPE is irreversiblyinhibited when rats are exposed to spectral bluelight (404 nm), leading to retinal damage.38 Narrow-band blue light of wavelength 439 nm disrupts theretina--blood barrier most severely.210
Interestingly, blue light has no effect on retinaswhen rhodopsin regeneration is inhibited by thedepletion of protein RPE65.91 Recent studies in-dicate that monochromatic blue light (403 nm) caninduce what is known as the photoreversal ofrhodopsin bleaching in vivo. In vivo exposure todeep blue light at 403 nm regenerates approxi-mately 30% of the rhodopsin after it has beenbleached by green light (550 nm).89 Exposure togreen light under the same conditions causes nodamage, whereas massive apoptotic cell death takesplace in retinas exposed to blue light. The authorssuggest that a long-lived photoproduct that absorbsblue light is generated from rhodopsin, and thisphotoproduct photoregulates rhodopsin when itabsorbs blue light.92 Indeed, ascorbate protectsagainst retinal damage caused by green light ratherthan that caused by blue light under otherwisesimilar experimental conditions, and this supportsthe conclusion that blue light is the most hazardouscomponent of the visible spectrum to the retina forthe induction of photochemical damage.188,293
Recent studies have focused on components ofthe RPE lipofuscin that may be chromophores thatparticipate in initiating or promoting light damage.
Sensitivity to blue light is significantly enhanced bythe accumulation of lipofuscin in cultured RPE cellsthat are fed on photoreceptor outer segments, andthese cultured cells have lower lysosomal membranestability and cell viability.286 A2E, a major fluoro-phore of the retinal pigment epithelial lipofuscin,has an excitation maximum at approximately 430nm.236 A2E is detrimental to the function of RPEcells, inhibiting the degradative capacity of theirlysosomes, reducing their membrane integrity, andincreasing their susceptibility to phototoxicity.224
Suter et al have reported that A2E induces apoptosisin the RPE at concentrations found in the humanand rat retina by targeting enzymes in themitochondria, particularly cytochrome oxidase.248
Sparrow et al found that A2E mediates bluelight-induced apoptosis of the RPE, which involvesthe activation of caspase-3; this process is inhibitedby Bcl-2.233,235 The damage of the RPE that containsA2E is greater when oxygen is present, althoughquenchers and scavengers of singlet oxygen provideprotection against this damage.238 DNA is damagedby blue-light illumination when oxidized purine,guanine, and pyrimidine bases in the A2E-ladenRPE are present.237 A2E may therefore play asignificant role in RPE phototoxicity. Indeed, theintraocular lens, which effectively absorbs blue light,significantly reduces the incidence of death ofA2E-laden RPE cells in culture.234
All-trans-retinal, a product of rhodopsin bleachingthat has an absorption peak at 387 nm, is one of themost abundant retinal photosensitisers.56 The mol-ecule can be excited by UV or blue light, and it canthen undergo efficient intersystem crossing, leadingto the formation of a triplet state and the release ofseveral free radicals. 218 All-trans-retinal acceleratesthe formation and the accumulation of lipofuscin-like material in the RPE.115--117,270 Further, photo-excited retinal inactivates the ATP-binding cassettetransporter (ABCR), which is involved in therecycling of all-trans-retinal, and this results in A2Eaccumulating in RPE cells.247 Thus, all-trans-retinalposes a potential risk of photochemical damage byboth UV and blue light in the outer segment andthe neighboring RPE.
Lipofuscin accumulates in young eyes and vastamounts of it are present, particularly in themacula.57,62,70,266 Its sensitizing action might, forthis reason, be fundamental to human disease.The amount of lipofuscin in RPE cells increasesduring ageing, and we expect that aged eyes willbe more susceptible to the blue light hazard. Anevaluation of the phototoxicity of lipofuscin forthree age groups has shown that the potential forblue light damage increases nine-fold during thelife-span.161
PHOTOCHEMICAL DAMAGE OF THE RETINA 473
Aging has little effect on the number of conephotoreceptors in the human fovea, whereas thenumber of parafoveal rod photoreceptors decreasesby 30% with increasing age.51 The spatial distribu-tion of lipofuscin generally matches that of rods,and it has the same pattern of age-related loss as thatof the rods.58,289 An early and severe rod loss, anadditional 30--40% being lost, takes place inadvanced AMD, with significantly reduced scotopicsensitivity in the macula.50,199 Thus, early rod loss isa characteristic feature of aging and of AMD,reflecting a continuum from aging changes todisease. It is possible that some primary defects thataffect the rod photoreceptors contribute to thedevelopment of AMD. The vulnerability of photore-ceptors to exposure to blue light and the role oflipofuscin in the photochemical lesions in the RPEthat result from phototoxicity support the hypoth-esis that light irradiation, aging changes in theretina and retinal degeneration are all related.162
D. CELL DEATH IN PHOTOCHEMICAL RETINAL
DAMAGE
Cells die by one of two processes, known asapoptosis and necrosis. These processes have beendefined morphologically and biochemically. Theterm apoptosis, coined as a description of cell deathin 1972 by Kerr, is from a Greek root that refers tothe dropping or falling of leaves from a tree.120 Themorphologic features that characterize apoptosisinclude cytoplasmic blebbing, chromatin condensa-tion, nuclear fragmentation, cell rounding (loss ofadhesion), and cell shrinkage. Cells undergoingapoptosis fragment into membrane-bound apopto-tic bodies, which are ingested by phagocyticcells.244,296 In contrast, necrosis involves the lysisof cells and organelles, and collateral tissueresponses.80,82
Apoptosis is an epiphenomenal event or the causeof a number of pathological conditions in theretina. It is interesting that apoptosis occurs in theprimate macula at similar rates at all ages.132 Cells ofthe RPE and photoreceptors die by apoptosis inAMD. Most apoptotic cells are located at the edgesof areas of atrophy, and in correlation with clinicallyobserved expansion of geographic atrophy.64 In vivodelivery of broadband blue light in the spectralrange 400--480 nm primarily induces apoptosis ofphotoreceptor cells. Such delivery induces the deathof RPE cells as a secondary process.293,295 Lipofuscinexcitation by blue light also accelerates the rate ofRPE apoptosis.233 Retinal damage induced by lightat other wavelengths also involves apoptosis.2,93
Further, the apoptosis of retinal cells as a consequenceof photic injury under a variety of experimental
conditions proceeds by both caspase-dependent andcaspase-independent pathways,61,90,294 suggestingthat many mechanisms operate in photochemicalretinal damage. There is, however, one commonpathway that is defined morphologically by the termapoptosis.
VII. Summary
Visual perception occurs when radiation witha wavelength between 400 and 760 nm reaches theretina. Photoreceptor cells are differentiated post-mitotic retinal neurons that are uniquely adapted tocapture photons efficiently and to initiate visualtransduction. Photoreceptors are normally sub-jected to incident light, and are maintained in anoxygen-rich environment to satisfy the high meta-bolic demand of these cells (which is higher thanany other cells in the body). There is thus a seriousrisk of light damage to photoreceptors.
We are now beginning to learn how acute lightexposure and chronic light history can affect thelong-term visual capacity. However, descriptions oflight damage are often inconsistent, and a numberof factors can modify the damage. These effectsensure that photochemical retinal damage cannotbe classified in a simple manner. Several types ofphotochemical retinal damage may exist or co-exist.The complexity of light damage makes it crucial todefine properly the experimental regime used whenstudying retinal light damage. One example is thespectrum of the light source used. Fluorescentsources that mimic the spectral qualities of daylightare used in many studies, and conclusions based onstudies using white light may differ from those fromstudies using narrowly defined wavelengths.
Photochemical damage of the retina has beenrecognized for several decades. Many aspects of lightdamage remain elusive, and the biological mecha-nisms of the damage are particularly unclear.Modern techniques of molecular biology havebecome available in recent years that allow bioen-gineered animal models (e.g., transgenic animals,knock-outs) to be constructed. These models havebeen helpful in clarifying the mechanism of lightdamage.37,40,91,166,178,185
A light-damage model has been increasinglyemployed to describe how the retina degenerates.This model has been used to investigate themechanism of programmed cell death and to testpotential rescue strategies, such as the administra-tion of antioxidants, drugs, growth factors, andother neuron-protective agents. LaVail et al firstdemonstrated that the neuron survival agents(bFGF, CNTF, BDNF, etc.) can ameliorate retinal
474 Surv Ophthalmol 51 (5) September--October 2006 WU ET AL
light damage.68,136,140 The expression of suchsurvival factors is up-regulated in focal mechanicalinjury, following systemic administration of the a2-adrenergic agonists xylazine and clonidine, andfollowing preconditioning of the retina with lightbefore exposure to harmful levels of light, a processthat can protect against retinal light dam-age.150,276,277 New techniques of pharmaceuticaltherapy and gene therapy require methods for theeffective delivery of a number of neuroprotectiveagents to the retina, and for the delivery of genesand their products that are known to be neuro-protective.39,114,133
It is well-known that blue light is detrimental tothe retina. The crystalline human lens normallyprevents much of the blue light from reaching theretina, but lens removal during cataract surgery andthe subsequent implantation of an intraocular lensthat filters UV light exposes the retina to a high riskof blue light-induced damage. The use of anadditional blue light filter should be considered,although it is unclear whether blue light predisposesan individual to the development of AMD or onlyexaggerates a property that is already present.
VIII. Method of Literature Search
The literature review described here was based ona comprehensive search of the PubMed database(www.ncbi.nlm.nih.gov/) from 1965 until August2004. The terms eye or retina or retinal pigmentepithelium or photoreceptor or age-related macular de-generation or lipofuscin in combination with the termsoptical radiation or radiation damage or light damage orphotochemical damage or blue light were used fora broad search and a sensitive search. This primarysearch was completed by checking the referencesand the references of the references cited inresearch articles and in review articles. Furthermore,books cited in these articles were used. Non-Englisharticles were included when necessary.
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The authors reported no proprietary or commercial interest inany product mentioned or concept discussed in this review. Thewriting of this review was funded , in part, by Torste och RganarSoderberg Foundation, Edwin Jordan’s Research Foundation,Vision Improvement Research Foundation, Crown PrincessMargareta’s Foundation for Vision Injury, Carmen och BertilRegner’s Eye Disease Research Foundation and KarolinskaInstitutet’s Research Funds.
Reprint address: Jiangmei Wu MD, PhD, Department ofVitreoretinal Diseases, St Erik’s Eye Hospital, Karolinska Institu-tet, Polhemsgatan 50, SE-112 82 Stockholm, Sweden.
Outline
I. The retinaII. Optical radiation and the eye
A. The electromagnetic spectrumB. Propagation and absorption of optical
radiation in the eyeC. Quantities and units
III. The nature of light damage in the retina
A. Photomechanical damageB. Photothermal damageC. Photochemical damage
PHOTOCHEMICAL DAMAGE OF THE RETINA 481
IV. General aspects of photochemical retinaldamage in animals
A. A morphologic description of photochem-ical retinal damage
B. Classifications of photochemical retinaldamage
C. Susceptibility factors identified in animalstudies
1. Wavelength2. Light intensity and exposure duration3. Cumulative effects of light4. Circadian rhythm5. Adaptive state6. Photosensitizing drugs7. Aging8. Genetics
a. Ocular pigmentationb. Species
c. Animal models of human retinaldegeneration
V. Photochemical retinal damage in humans
A. Short-term and long-term exposure tosunlight
B. Iatrogenic exposure to lightC. Impact of light exposure on age-related
macular degeneration
VI. Mechanisms of photochemical retinal damage
A. Chromophores probably involved in theinitiation of retinal damage
B. The role of photooxidation in retinal damageC. Blue light--induced retinal damageD. Cell death in photochemical retinal dam-
age
VII. SummaryVIII. Method of literature search