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Mmubn000001 026689529.Pdf PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/147957 Please be advised that this information was generated on 2021-09-24 and may be subject to change. OXIDATIVE CHALLENGE TO AGING HUMAN LENS LEADING TO NUCLEAR CATARACT P.M.M. van HAARD TOELICHTING Het doel van het hier beschreven onderzoek is een beter inzicht te krijgen in het ontstaan van cataract o-F staar in de ooglens van sommige ouder wordende mensen. De lens stelt de mens in staat om scherp te zien. Een voor­ waarde is wel dat de lens licht doorlaat. Elke verandering in de lichtdoorlaatbaarheid ten gevolge van troebel worden van de lens wordt cataract genoemd. Oit betekent niet dat onscherp zien altijd aan cataract te wijten zou zijn. De lenstroebelingen, voorkomend bij oudere mensen (90-95% van alle cataracten) worden ouderdomscataracten genoemd. Tot deze groep van cataracten behoort de kerncataract ι het is de­ ze vorm van cataract die ik onderzocht heb. De kerncataract is om allerlei redenen een interessant onder- zoekobject. Komen bij andere ouderdomscataracten witte troe- belingen voor in verschillende delen van de lens, bij kernca­ taract wcrdt alleen het normaal lichtgeel gekleurde binnenste deel van de lens - de kern - meestal rond het vijftigste jaar steeds harder, troebel en bruiner van kleur. In het ernstigste en meest gevorderde stadium blijkt de harde, zwartbruine kern van de lens even groot te zijn als de lens bij de geboorte is. Tot op heden blijkt de enige therapie te zijn een operatief ingrijpen, waarbij de lens verwijderd wordt en het gezichts­ vermogen redelijk hersteld met een contactlens of een bril, voorzien van zeer dikke glazen. Het is logisch dat met toene- mende medische controle eerder zal worden ingegrepen) er zul­ len in de toekomst ook minder zeer ernstige kerncataracten be­ schikbaar komen voor onderzoek. De ogenschijnlijk onbeduidende bevinding dat de cataract groter wordt met het bruiner worden van de kleur, heeft belang­ rijke gevolgen gehad voor mijn onderzoek. Alvorens dit te kun­ nen uitleggen moeten we eerst meer weten over de ontwikkeling en veroudering van de lens. De lens ontwikkelt zich voor de geboorte, aanvankelijk als een rond bolletje, de embryonale lens, waaromheen zich langgerekte cellen vormen, enigszins vergelijkbaar met de rokken van een ui. Het resultaat van deze ontwikkeling is dat de buitenlaag van de lens - de cortex - jonger is dan het binnenste gedeelte, de kern. Op elk moment in het leven van de mens is het binnen­ ste deel van de lens even oud als de mens zelf. Om alle cellen van de lens bij elkaar te houden, zit er om de lens een elastisch vlies, het kapsel, en via dit omhulsel is de lens verbonden met spieren die de lens van vorm doen ver- andereni dit proces wordt accommodatie genoemd. De lenscellen zitten boordevol eiwitten, die zo dicht en toch ook weer zo geordend gestapeld zijn dat elke cel in staat is licht dat erop valt van richting te doen veränderen) dit pro­ ces wordt lichtbreking genoemd. Accommodât ie en lichtbreking zorgen voor scherp-zien. Via het kapsel krijgt de lens voedingsstoffen toegevoerd, uit een met vocht gevulde ruimte voor de lens, de voorste oogkamer. Een eiwit bestaat uit onderling verschillende bouwstenen, de aminozuren, dia de vorm, grootte en andere eigenschappen en daarmee de funktie van het eiwit bepalen. De funktie van de lenseiwitten is vrij duidelijk: ze moeten struktuur geven aan de lenscellen en daarmee dus aan de lens. Over het ouder wor­ den van deze eiwitten, van het celomhulsel (membraan genoemd), over stoffen in de lens die de bestanddelen van de lens een leven lang beschermen of daarin tekort schieten, en over an­ dere mogelijke oorzaken voor het ontstaan van kerncataract handelt dit proefschrift. Aangezien de lens een leven lang licht moet doorlaten, is het aannemelijk dat zonlicht een oorzaak kan zijn voor het ontstaan van kerncataract. Niet alle zonlicht is schadelijk voor de lensi het is mogelijk dat brildragers of binnenshuis werkenden beter beschermd zijn dan andere mensen die het moeten hebben van de lagen rond de aarde en de bescherming door het hoorn­ vlies tegen schadelijk licht van de zon. Het valt op dat op plaatsen waar de mens bloot gestald is aan vele zonneuren (Thailand, Pakistan, Cambodja) meer kerncata­ racten voorkomen dan in onze streken. De vraag rijst echter waarom kerncataract ook in zonnige streken pas op hogere leef­ tijd optreedt en waarom niet overal in gelijke mate. Da lens groeit gedurende het hele leven binnen het kapsel: de buitenste delen (jong materiaal) worden tegen de gevolgen van schadelijk licht hoofdzakelijk beschermd door bepaalde ei­ witten, enzymen, terwijl de binnenste lagen bijna uitsluitend beschermd worden door stoffen die vrijer kunnen bewegen dan eiwitten. Uit mijn onderzoek bleek dat in de binnenste delen van de lens de concentratie van die vrije stoffen afneemt naarmate men ouder wordt en dat die afname schrikbarend groot is in len­ zen met kerncataract. Ik heb alleen onderzoek kunnen doen aan lenzen uit Duitsland en Nederlandi wanneer men afgaat op de klaur van deze cataracteuze lenzen en die uit Pakistan blijkt dat mensen in Pakistan op jongere leeftijd kerncataract krij­ gen dan in onze streken. De faktor zonlicht speelt hier ver­ moedelijk een rol. In het kort komt het er vervolgens op neer dat er met de af­ name van de concentratie van beschermende stoffen beschadigin­ gen optreden in de eiwitten van de binnenste cellen van de lens. Het proces van verkleuring en troebeling start daarom in het oudste deel van de lens: de embryonale lenskern en spreidt zich uit met het donker worden van de kleur, naar bui­ ten toe. De termen die voorkomen in de titel van dit proefschrift worden hiermee al een stuk duidelijker: "challenge" betekent in eerste instantie "uitdaging" en met de toevoegingen "oxi­ dative" en "aging" wil ik aanduiden dat die uitdaging op den duur tot een beschadiging van verouderde lenscomponenten ten gevolge van een oxidatieproces leidt. I\lu kan zuurstof niet ver­ antwoordelijk zijn voor deze oxidatie, omdat het praktisch niet voorkomt in de lens. Het zoeken naar stoffen die hetzelfde ef- fekt kunnen hebben als zuurstof werd versneld door bepaalde be­ vindingen in dit promotieonderzoek "waarbij, afgaande op de struktuur van oxidatieprodukten, kon worden afgeleid dat water­ stofperoxide een rol zou kunnen spelen bij het ontstaan van kerncataract. De vraag is daarmee niet opgelost, want wij moe­ ten nog te weten komen waar dat waterstofperoxide vandaan komt. Wij veronderstellen dat een bepaalde bouwsteen van de lens- eiwitten lichtenergie in zich opneemt en daarbij niet in brok­ stukken uiteenvalt, maar die energie overdraagt aan natuurlij­ ke beschermers die aanvankelijk in overvloed aanwezig zijn. Langzamerhand verdwijnen deze beschermende stoffen bij het ver­ vullen van hun taak, en zo zal op den duur energie worden over­ gedragen aan eiwit en andere bouwstenen van de lens, met scha­ delijke gevolgen voor de lens en de eiwitten daarin. Dit proces treedt in de lens bij hoge leeftijd op. De ei­ witten klonteren samen, hetgeen tot troebeling en verkleuring leidt. Het samenklonteren van de eiwitten heeft mogelijk tot gevolg dat de celmembranen van struktuur veranderen zonder dat deze zelf door zonlicht etc. zijn aangetasti de aanvankelijk soepele membranen van de lenscellen ondergaan wel - tijdens veroudering - een aantal veranderingen in samenstelling, die het hele cataracteuze proces kunnen versnellen. üe oorzaak van de verkleuring van de lenskern heb ik maar ten dele kunnen ophelderen, aangezien het onderzoeken van on­ ontwarbaar materiaal speciale technieken vereist die duidelijk tekortkomingen bezitten. Wanneer je met chemische middelen niet verder kunt doordringen in de materie, kun je nog afbre- kende stoffen (bepaalde enzymen) gebruiken die door de natuur ontworpen zijn om alleen natuurlijke stoffen aan te vallen (of er nuttige stoffen van te maken). Blijkbaar zijn de facetten van kerncataract niet natuurlijk en zijn de samengeklonterde eiwitten uit de lens te vergelijken met zwarte, zich opstape­ lende stoffen die ook voorkomen in andere, langlevende, cellen van het menselijk lichaam, zoals de hersencellen. Een tweede belangrijk punt bij het beschrijven van kernca­ taract en de moeilijkheden van onderzoek daaraan is dat, tij­ dens kerncataract, de normale veroudering van de lens doorgaat met zijn eigen specifieke verschijnselen. Het is dus onjuist te veronderstellen dat kerncataract een vorm van versnelde ver­ oudering is: de verschijnselen die optreden bij kerncataract zijn ten dele te vergelijken met normale veroudering, omdat normale veroudering kan leiden tot kerncataract, afhankelijk van invloeden van buitenaf, bijvoorbeeld zonlicht. Kerncataract zou teruggedrongen kunnen worden, al moeten we wel minstens 40 jaar op de resultaten wachten, totdat de mens in zonrijke streken beter voedsel beschikbaar had en zijn ogen voortdurend kon beschermen tegen zonlicht. Wij zullen ook in dit opzicht zuinig moeten zijn op de beschermende ozonlaag rond de aarde die steeds meer aangetast lijkt te worden door uitlaatgassen van vliegtuigen en drijfgassen uit spuitbussen. Nijmegen, 16 september 1980 P.M.M, van Haarci OXIDATIVE CHALLENGE TO AGING HUMAN LENS LEADING TO NUCLEAR CATARACT Promotores: Prof. Dr. H.J. Hoenders Prof. Dr. H. Bloemendal Coreferent: Dr. J. Haverkamp OXIDATIVE CHALLENGE TO AGING HUMAN LENS LEADING TO NUCLEAR CATARACT
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