Ординатура / Офтальмология / Английские материалы / Progress in Lens and Cataract Research_Hockwin_2002

errors or misunderstandings in the lens research community, thus preventing a better outcome of the enormous investment of work and money. First of all I would like to discuss the fact that the topography of lens metabolism is not taken account of when total lenses are analyzed. The usual way of starting an analysis of a lens is the homogenization of the total lens to obtain a water-soluble or acid-soluble extract of the ingredients. It has been known already for a long time that there are remarkable differences in the composition of the lens between the outer layers and the nucleus. This was demonstrated by histochemical methods or by separating single lens layers before homogenization [13–19].

The homogenization of the total lens is in no way the state of the art for establishing biochemical properties of the lens; it is just a mechanical averaging (by homogenization) of the ingredient substances. The results obtained are wrong, because they assume that all substances are distributed homogenously within the lens. The vast majority of data published on changes of compounds in the lens with a formation of cataracts are without relevance; different approaches as demonstrated by Hockwin, Kojima or Horwitz and colleagues [20–27] have to be adopted.

The same applies to the many investigations of the ageing of the total lens but different ages of the single layers. Most age-related changes of lens biochemistry were obtained by analyses of young versus old lenses (several authors did not even consider the life expectation of the species) as differentiated by the wet weight of the lens. A young rat lens of 6 weeks has a wet weight of about 20 mg; this is about doubled at the age of 16 weeks. The life expectation of the rat is about 3.5 years; the wet weight of the lens at this time is about 65–70 mg in male and 60–65 mg in female Wistar rats. Determining the biochemical constituents of an old rat lens does include about three quarters of its lens weight which was not at all present in the young lens; thus the results do not represent the ageing of the young lens. All one would be able to compare is the composition of the superficial layers, or of the cortical layers or of the inner part (nucleus) at different ages. Looking then at the values of the nucleus one could say something about the influence of ageing of the young lens (the young lens is still the nucleus of an old lens!). But for the cortex or for superficial layers one does not determine the ageing of these parts, rather the influence of age in the formation of these layers during the postnatal period. In other words, comparing superficial or cortical layers of lenses of different ages means to investigate the influence of the age of epithelial cells on their capability to differentiate and elongate (protein synthesis) to new lens fibers. It is already known that-crystalline is missing in the superficial layers of 4- to 5-year-old bovine lenses [16, 17]; the quality of the protein synthesis has changed already in younger animals (life expectation about 25 years!) by losing its capacity to synthesize the smallest protein fraction.

Analyses of the total lens are also obsolete in the frame of pharmacokinetic studies of the drug penetration into the lens. Only the concentration in the anterior outer lens layer is representative; in most cases the drug in question does not penetrate into the lens nucleus. Measuring the total lens gives then much too low values for the outer cortical layer, a procedure which is still used by the preclinical toxicity studies of most pharmaceutical companies; the method published by Kojima et al. [28–30] would be better.

Another point of misunderstanding is related to lens opacities in older humans. The diagnosis of the ophthalmologist of ‘senile cataract’ has spread the opinion that ageing of the lens is the only cause for the disease. There were multiple approaches during the 1970s and 1980s to locate the age-induced changes of lens metabolism responsible for cataract formation. Unfortunately these investigations were performed with unclassified lenses; nobody realized that there are several distinct types of cataracts in the elderly population or classified lenses were analyzed in toto, again a mechanical averaging of the lens constituents not regarding size and intensity of the opacified area in relation to the still transparent parts of these cataract lenses. The progress of cataract surgery introducing the extracapsular cataract extraction by destruction of the cataractous lens with the aid of sonic energy ended these fruitless approaches.

Several findings of lens metabolism regarding the posttranslational changes of lens proteins including enzyme activities [18] and the effect on energy metabolism as well as the findings with experimental cataracts about synand cocataractogenic mechanisms [31–33] supported by the first properly performed epidemiological studies [34–36] made a change of our ideas about the pathogenesis of the ‘so-called senile cataract’ necessary. Senile cataract has a multifactorial pathogenesis with different distinct types of opacities [37, 38].

Epidemiological studies have elaborated several risk factors participating in the process of opacification with synor cocataractogenic mechanisms. The variety of risk factors and the variety of possible cumulations among them are responsible for the different types of opacities. The old question of whether ageing of lens metabolism is the only cause for cataract and why we have such different cataract ‘morphologies’ can be answered meanwhile with the accepted concept of a multifactorial pathogenesis of human cataracts.

True Diabetic Cataract (von Graefe [39] in 3858) and So-Called Senile Cataracts in Diabetic Patients (‘Senile Diabetic Cataract’ – A Nonsense Diagnosis)

In the early 1980s research centered around the development of inhibitors of the enzyme aldose reductase in order to prevent the formation of the polyol

sorbitol, which was shown to be the source of the development of the true diabetic cataract with a very specific expression of the opacities. After basic laboratory work was able to show the mechanism of the sugar cataract formation [40, 41] involving the sorbitol pathway, the development of inhibitors for the triggering enzyme aldose reductase seemed to open the possibility for prevention of this type of cataract. A great series of such inhibitors were developed and tested successfully in animals.

At this point unfortunately one of the biggest errors in lens research occurred. Unaware of or not remembering the previous observations, having started as early as 1858 by von Graefe [39] or others (as quoted extensively by Koch et al. [42]) that high blood glucose concentration acts on the lens in different ways depending on the age of the patient, mainly US ophthalmologists started to define cataracts in elderly patients with diabetes as ‘senile diabetic cataracts’ and locked for a treatment with aldose reductase inhibitors to prevent opacification or to stop further progression. It is correct that the frequency of cataracts among elderly diabetic patients is higher than in nondiabetic patients of the same age [43], but the type of opacifications does not differ between diabetics and nondiabetics. Keeping in mind the multifactorial pathogenesis this is a proof that diabetes is an additional risk factor for cataract development; the possible (still unknown) mechanism, however, is completely different from that in the true diabetic cataract of young diabetic individuals involving the sorbitol pathway.

On top of this error the pharmaceutical companies were happy for the opportunity to test their aldose reductase inhibitor compounds as eye drops in controlled clinical trials to establish their efficacy in the treatment of senile diabetic cataracts. The end of this development came very suddenly through the occurrence of systemic adverse effects, in one trial even causing the death of participating patients. It is not known how much research money and how much labor have been wasted because old observations documented in the literature were no longer known or were interpreted incorrectly. Hopefully it is possible to avoid a repetition of a similar disasters in the new century.

Use of Normal Animal Lenses or Experimental Cataracts Does Not Take Account of Species Differences of Lens Properties

Using animal eyes to investigate problems and mechanisms of the human eye also has a long-standing history. Bouchard and Charrin [44] reported as early as in 1886 on their experiments with naphthalene cataracts in rabbits, this probably being the oldest paper on induced cataract in an animal with the intention to study similar mechanisms in the human eye. Only a few years later

Widmark [45] (1889) reported on experiments with rabbits to study the effect of UV radiation (he still called it ‘(sun)light’) on the anterior eye segment. Many experiments followed during the first half of the last century, producing a variety of cataract types in a variety of animal species. Peculiar effects were found in that one and the same compound produced different types of cataracts depending on the species selected for the experiment. It was not before the mid 1950s, however, that specific research was carried out into the importance of species differences and their influence on cataract development. Again the naphthalene cataract model was helpful in demonstrating the tremendous difference between two species, the reaction of the rabbit lens (mature cataract) and the rat lens (zonular cataract). Another example is the type 1 diabetic cataract, which can easily be induced in rats, but not in mice, simply because of one essential species difference: the activity of aldose reductase. In the rat lens, its activity is comparable to the human lens; thus enough sorbitol is produced to trigger the formation of a true diabetic cataract. In mice, in contrast, the activity is too low to induce any changes in the lens.

Such species differences are of paramount importance in all animal studies in lens and cataract research and there were many misunderstandings in transferring results from animal to man because species differences were not taken account of. Detailed protein chemical investigations in the 1960s [6, 18] were instrumental in elaborating species differences on the level of lens crystallines, but there are important differences in many eye tissues [46]. This includes in particular the aqueous humor dynamics, which can have an important impact on the kinetic properties of a drug in the anterior eye segment, especially the lens.

Influence of Eye Pigmentation on Conditions of Lens Properties

Unfortunately, professional animal breeders developed a selection of albino rat, mouse and rabbit strains for research purposes, but it has taken a lot of effort to convince the eye research community that albino eyes are sick eyes, and thus unsuitable for meaningful eye research, because whatever results are transferred to humans, the human eye is pigmented [47]. Not only do sensitive tissues in the eye receive damaging amounts of light in albino eyes, there is also the melanin metabolism which is missing, a feature potentially having a prominent effect on drugs and their action in the eye. One effect is certainly different, when comparing albino and pigmented eyes, that is albino eyes have much less binding and storage capacity for drugs. Thus a compound studied with respect to its kinetic properties in the albino eye may have a much lower drug level and a much faster turnover than it will have in the pigmented human eye later.

Consequently data obtained from such investigations produce a dangerous kinetic profile by simulating a much shorter half-life of drugs in the eye than will be present in their clinical application.

In the 1950s for about 2 decades lens research of very different aspects was done as in vitro studies neglected the influence of aqueous humor dynamics on lens conditions. The use of many different incubation media made it almost impossible to compare data of different laboratories. It was only in 1972 during a meeting of a group preceding the ICER (International Committee of Eye Research) in Charleston, S.C., USA that an agreement was reached to use the medium TC 199 for future lens incubation studies. The in vitro research then gave a good insight into ways of transportation, of capsule permeability, of electrolyte exchange, of temperature influences on transport and metabolism and also into problems of pharmacokinetic of drugs and their distribution in the lens. With the use of radiolabeled amino acids in long-term culture systems even measurements of the protein synthesis rate became possible [48]. Ignoring eye pigmentation and its possible influence on lens metabolism was widespread in in vitro studies; the origin of the isolated lens was not deemed important.

At the beginning of the 1980s most laboratories returned to in vivo lens studies. Only a few groups moved on to in vitro epithelial cell tissue culture methods, a strong instrument for basic problems such as cell differentiation, elongation and protein synthesis [49–51] with a high potential of useful applications in preclinical studies to control possible toxicity of new drug developments.

The new wave of in vivo lens studies – mainly the research of experimental animal cataracts – was affected for a long time by the complete failure of the scientists to recognize the importance of the aqueous humor and its composition for the properties of the lens, and they also only slowly became aware of the influence of eye pigmentation.

Our list of errors and misunderstandings would be incomplete if we did not mention the comparison of lenses with and without accommodative capacity. Most of our lens studies are conducted with animals such as the mouse, rat, pigeon, chicken, guinea pig, rabbit, dog and only a few with primates. Bearing in mind the observations and calculations by Gullstrand [52] and the findings of Kleifeld [53] of an intracapsular accommodation mechanism with active participation of metabolic processes, we have to admit that most of our animal lenses do not have an accommodative capacity at all. It has to be assumed that a lens with accommodative power has a metabolic pattern similar to a muscle (ratio ATP/ADP 8), whereas the other nonaccommodative lenses rather correspond to the metabolic pattern of the liver (ratio ATP/ADP 3). Only a few investigations have been performed in this direction [54]. As the outcome of the dinitrophenol cataract by inhibiting the oxidative phosphorylation of the

carbohydrate breakdown showed cataracts in humans and birds [55], but not in rats, rabbits and dogs [56] we probably should pay some more attention to this very neglected property of lens accommodation.

At the end of this review we ask ourselves why it was possible that we have made these mistakes, and we have come to the conclusion that to a greater part the missing cooperation between clinicians and basic researchers might be responsible for the deplorable development. A great disadvantage is the missing cooperation between clinicians and epidemiologists on one hand and basic lens researchers on the other. Especially the ignorance of basic researchers regarding the clinical problems of the lens and of cataracts might be to blame for several ‘errors and misunderstandings’ mentioned above. There was a time when lens research done by clinicians was regarded as being of a low quality by the basic scientists. But on the other hand it is not very long ago since the introduction of slit lamp microscopical examination of animal eyes as an essential standard method for a basic lens research team which received intensive training in this method in a hospital setting.

Another disadvantage is still the use of the general diagnosis of cataract by the clinicians without further classification of the topography of the opacification, which supports the concept that a cataract is the one and only lens disease and all cataracts have the same trigger mechanism. (No clinician or patient would accept a diagnosis like ‘retina disease’ without further specification!)

But most regrettable is the fact that many clinicians have never really been interested in the basic research of the lens, in cataract pathogenesis and epidemiology of risk factors or in testing the efficacy of cataract-preventing medication [57]. Their main goal is and has been cataract surgery with improving techniques and the lens replacement with intraocular lenses. As a result of the success of cataract surgery at the present time clinicians even express the opinion that lens and cataract research is no longer necessary to overcome cataract blindness. But as we all know this refers only to highly industrialized countries, whereas worldwide millions of cataract-blind people are still without such help and a change of this condition is not in sight. Whether basic research in the future will be able to improve the chances for help will strongly depend on the question of whether we have learned from the errors of the past: so let us all do some homework!

In our opinion lens and cataract research is still necessary and we are convinced it will be more successful if we bear in mind the mostly unintentional errors of the 20th century but keep them out of our future research work.

If you look at the age of the authors then you know who is responsible for the major part of the errors and misunderstandings presented. But I (O.H.) am very glad that my younger coauthors are scientists who helped the ‘older generation’ elucidate its wrong approaches and find the new ways which promise

better results in the future. I wish them and the worldwide lens community good luck for the continuation of their research in the 21st century for the benefit of our patients.

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Prof. Dr. Dr. h.c. Otto Hockwin,

Tulpenweg 4, D–53757 Sankt Augustin (Germany)

Tel. 49 2241 203048, Fax 49 2241 27525, E-Mail otto.hockwin@t-online.de

Hockwin O, Kojima M, Takahashi N, Sliney DH (eds): Progress in Lens and Cataract Research. Dev Ophthalmol. Basel, Karger, 2002, vol 35, pp 12–20

Risk Factors for Nuclear Lens Opacification: The Reykjavik Eye Study

Arsaell Arnarssona, Fridbert Jonassona, Hiroshi Sasakib, Masaji Onoc,

Vesteinn Jonssona, Masami Kojimab, Nobuyo Katohd, Kazuyuki Sasakib,

Reykjavik Eye Study Group

aDepartment of Ophthalmology, University Hospital, Reykjavik, Iceland;

bDepartment of Ophthalmology, Kanazawa Medical University, Kanazawa,

cNational Institute for Environmental Studies, Tsukuba, and

dDepartment of Public Health, Juntendo University, School of Medicine, Tokyo, Japan

Abstract

Purpose: The purpose of this study is to examine risk factors for nuclear lens opacification in citizens of Reykjavik.

Methods: 1,045 persons, 583 females and 462 males aged 50 years and older, were randomly sampled and underwent a detailed eye examination and answered a questionnaire. In all Scheimpflug photography of the anterior eye segment was done including the lens as well as retroilluminated photography of the lens. These photographs were used for the diagnosis of lens opacification. The data was analyzed using a logistic regression model.

Results: An increased risk for all grades of nuclear opacifications was found with ageing (OR 1.228, 95% CI 1.192–1.264, p 0.000), cigarette smoking for more than 20 pack/years (OR 2.521, 95% CI 1.521–4.125, p 0.000) and pipe or cigar smoking (OR 2.478, 95% CI 1.200–5.116, p 0.014). Outdoor exposure, cortical lens opacification grade II and III and computer usage were not found to be linked to higher risk of nuclear opacification. No correlation was found between nuclear opacification and the consumption of vitamins, herring, sardines and shrimps, cod-liver oil or plant oil, nor were iris color, hyperopia, systemic steroid use, cardiovascular disease, diabetes, glaucoma and pseudoexfoliation found to have a significant effect.

Conclusions: Ageing is a major risk factor for nuclear lens opacification, and smoking is a major modifiable risk factor. Cortical and nuclear lens opacifications do not share the same modifiable risk factors.

Copyright © 2002 S. Karger AG, Basel