Ординатура / Офтальмология / Английские материалы / Ocular Therapeutics Eye on New Discoveries_Yorio, Clark, Wax_2007

levels were detected in aqueous humor (Zhang et al., 2003). Few explanations, other than exposure to sex hormones, have been offered for the consistent positive association between female sex and age-related cataracts. Understanding the basis for this difference should be a primary goal of cataract biology.

D. Risk of Nuclear Cataracts: Smoking

A major, modifiable risk factor for nuclear cataracts in many epidemiologic studies is smoking. Smoking is not usually identified as an independent risk factor for cortical or PS cataracts. A recent review of 27 studies suggested that the evidence linking smoking and nuclear cataract (dose response, temporal relationship, and reversibility of effect) was sufficient to infer a causal relationship (Kelly et al., 2005). Individuals in rural populations are often exposed to cooking smoke, which has also been linked to nuclear cataract formation (Mohan et al., 1989; Pokhrel et al., 2005). However, we do not know which components of smoke contribute to the disease, and whether this contribution is caused by a direct chemical reaction with lens constituents or an indirect effect resulting from the interaction of smoke constituents with some other part of the body. There may be a need for additional studies to examine the etiology of smoking as it relates to nuclear cataract, similar to those that have begun to examine the association between smoking and age-related macular degeneration (Brogan et al., 2005; Espinosa-Heidmann et al., 2006). However, from a public health perspective, the harmful effects of smoking are sufficiently numerous and well documented that reducing the number of smokers may be a more efficacious approach to managing this problem. Unless understanding the mechanism by which smoking contributes to nuclear cataract provides insight into the causes of nuclear cataracts in general, the relatively low priority that has been given this issue may be warranted.

A general group of risk factors for nuclear cataracts includes lower income, decreased education, poorer diet, or other measures of decreased socioeconomic status. Of these rather imprecise variables, the role of diet has received the greatest attention (reviewed in Chiu and Taylor, 2006). Numerous studies concluded that a diet rich in fruits and vegetables reduces the risk of all types of cataracts. However, attempts to reduce cataract incidence by supplementing with antioxidant nutrients have had minimal success, including large, welldesigned clinical trials (AREDS, 2001b; Meyer and Sekundo, 2005). Either a critical nutrient has been omitted from these trials or the correct mix of nutrients has not been identified. Since adopting a diet rich in vegetables and antioxidant nutrients would be beneficial for all aspects of health, including cataract prevention, increasing the overall quality of the diet may be a more efficacious goal.

E. Risk of Nuclear Cataracts: Myopia

Although myopia is commonly associated with nuclear and PS cataracts, investigators have cautioned that myopia can be the result of nuclear cataract formation, arising from the “myopic shift” that commonly precedes or accompanies the appearance of a clinically significant nuclear cataract (Brown and Hill, 1987; Lim et al., 1999). However, studies have shown that nuclear cataracts may be associated with elongation of the globe, the primary cause of myopia (Chen et al., 2003; Lin et al., 2004). Other studies have failed to detect an association between axial length and cataract (Wong et al., 2003). The association of refractive errors with cataracts of all kinds was reviewed recently (Saw et al., 2005). Although the etiology of myopia and nuclear cataract, if it exists, is largely unexplored, we have suggested that such an association could result from the effects of myopia on the structure of the vitreous body (Harocopos et al., 2004).

●The observation that loss of the gel structure of the vitreous body is a major risk factor for nuclear cataracts presents opportunities for therapeutic intervention. Replacement of the vitreous body with a synthetic gel would test, in animal models, whether restoration of the gel structure of the vitreous reestablishes the normal, low level of oxygen close to the lens. Follow-up studies in humans would reveal whether replacement of the vitreous gel prevented or slowed the formation of nuclear cataracts after vitrectomy. If successful in delaying cataracts after vitrectomy, this test would provide complete satisfaction of the three legs of Koch’s postulates with regard to the structure of the vitreous body and the formation of nuclear cataracts.

●In the future, methods could be developed to restore the vitreous gel in patients

who have early and extensive degeneration of the vitreous body. Alternatively, oxygen can be selectively depleted near the lens. To make these therapies effective, new methods are needed to non-invasively assess the extent of vitreous degeneration.

● The identification of genetic modifications that are associated with age-related cortical or nuclear cataracts will reveal the pathways that sensitize an individual to cataract formation. Modifying these pathways may protect the lens against cataracts. There is no reason to assume that these pathways will involve components only within or specific to the lens. For example, we predict that genetic alterations that decrease the stability of the vitreous gel will increase the risk of nuclear cataracts.

F. Risk of Nuclear Cataracts: Loss of the

Gel Structure of the Vitreous Body

Previousstudiesinourlaboratorydetected an association between the extent of degeneration of the vitreous body, sometimes termed vitreous syneresis, and increased opacification of the lens nucleus in postmortem human eyes (Harocopos et al., 2004). This association remained highly significant when results were adjusted for donor age. There was no correlation between the state of the vitreous gel and cortical or PS cataracts.

A more dramatic association between nuclear cataracts and the structure of the vitreous body occurs following vitrectomy surgery. Nuclear cataracts are well known to occur within 2 years after vitrectomy in more than 60% of patients older than 50 (de Bustros et al., 1988; Cherfan et al., 1991; Van Effenterre et al., 1992; Melberg and Thomas,

1995; Thompson et al., 1995; Cheng et al., 2001). Strikingly, retinal surgery that does not destroy the structure of the vitreous body does not cause the progression of nuclear cataracts (Saito et al., 1999; Sawa et al., 2001, 2005).

We suggested that breakdown or destruction of the vitreous body promotes the circulation of the vitreous fluid, thereby delivering increased amounts of oxygen from the surface of the retina to the lens (Harocopos et al., 2004). Previous studies showed that increased exposure of the human lens to oxygen during hyperbaric oxygen therapy is associated with a myopic shift and the rapid onset of nuclear opacification (Palmquist et al., 1984). Measurement of oxygen levels in patients at the time of vitrectomy revealed that oxygen levels near the lens were acutely high during surgery and then 30–40% higher than normal for

months after surgery (Holekamp et al., 2005). Reducing the oxygen levels in the infusion fluids used during vitrectomy might be an important first step in protecting the lens against nuclear cataract.

In a possible corollary, oxygen levels were significantly lower in the vitreous bodies of patients with diabetic retinopathy (Holekamp et al., 2006). Diabetics are reported to have lower age-adjusted rates of cataract surgery after vitrectomy than non-diabetics (Smiddy and Feuer, 2004), and diabetes has been associated with decreased prevalence of nuclear cataracts in epidemiologic studies (AREDS, 2001b).

Based on these data, we suggested that increased exposure of the lens to oxygen is a major risk factor for nuclear cataracts. Since this mechanism involves a change in the environment around the lens, rather than a defect in the lens itself, lowering oxygen levels around the lens should be amenable to therapeutic intervention.

Younger patients who have a vitrectomy develop nuclear cataracts much less frequently than older patients (Melberg and Thomas, 1995), suggesting increased sensitivity of the older lens to oxidative stress. As mentioned above, the rate of diffusion of glutathione and other small molecule antioxidants from the lens cortex to the nucleus decreases with age (Truscott, 2000). If increased exposure of the lens to oxygen contributes to nuclear cataract formation, decreased availability of reduced glutathione in the lens nucleus may help to account for the age-related increase in nuclear cataract formation after vitrectomy. In this view, age-related changes in the physical properties of the lens, combined with increased exposure to oxygen, account for the formation of age-related nuclear cataracts.

The hypothesis that loss of the gel structure of the vitreous body leads to increased exposure of the lens to oxygen and the formation of nuclear cataracts meets two requirements of Koch’s postulates and part of the third. We and others showed that

(1) oxygen levels around the lens increase

under conditions that lead to the formation of nuclear cataracts; and (2) increasing the exposure of the lens to oxygen is associated with the rapid formation of nuclear cataracts. The third requirement, that maintaining the structure of the vitreous body should decrease the incidence or slow the progression of nuclear cataracts, has been partially tested. Preserving the structure of the vitreous body completely protects against the formation of the nuclear cataracts that typically occur after retinal surgery (Sawa et al., 2005). It remains to be determined whether replacing the vitreous body or lowering oxygen levels in the eye after vitreous degeneration or destruction prevents the progression of nuclear cataracts. Since vitrectomy necessarily involves intrusion into the eye, the nuclear cataracts that follow retinal surgery in older patients provide an excellent model for testing these predictions. There is also a plausible sequence of events that connects increased oxygen exposure to the oxidative damage that causes nuclear cataracts (Harocopos et al., 2004; Shui et al., 2006). Finally, we predict that genetic alterations that reduce the durability of the vitreous gel will contribute to the inherited tendency to form nuclear cataracts.

G. Risk of Nuclear Cataracts: Lens Size

Epidemiologic studies identified a previously unsuspected risk factor for nuclear cataracts. Examination of participants in the Beaver Dam Eye Study, a long-term examination of the risks for several ocular diseases, showed that those with thicker lenses were more likely to have nuclear cataracts (Klein et al., 1998). Subjects who had larger lenses at baseline had increased risk of developing nuclear cataracts during a five year follow up study (Klein et al., 2000a). These observations naturally lead one to ask what factors might account for increased growth of the lens.

Several growth modulators that might alter lens size have been identified in

aqueous humor or in the tissues bordering the anterior chamber (Griep 2006). These include insulin and insulin-like growth factors, transforming growth factors, platelet derived growth factors, fibroblast growth factors, hepatocyte growth factor and epidermal growth factors. Although increases or decreases in one or more of these factors may account for increased or decreased lens growth, to our knowledge, the growthpromoting activity of aqueous humor has not been shown to vary with age.

Our recent studies found that the level of oxygen in the eye can control the growth of the adult lens (Shui and Beebe, submitted). When older rats or mice breathed 60% oxygen, instead of the 21% oxygen present in air, oxygen levels in the eye increased greatly and the rate of lens epithelial cell proliferation, lens fiber cell differentiation and lens growth increased significantly. If, as suggested above, the vitreous body maintains low oxygen levels around the lens, degeneration or removal of the vitreous body may indirectly increase the rate of lens growth. Increased lens size may, itself, be a risk factor for nuclear cataracts. Alternatively, oxygen exposure may directly promote nuclear cataract formation. In this case, increased lens size may simply be a side effect of increased exposure of the lens to oxygen. We think that it is likely that both are correct; oxygen causes increased oxidative damage in the lens nucleus, and increased lens size makes the lens more susceptible to this oxidative stress.

H. Risk Factors for Cortical Cataracts:

Sunlight

One of the best known risk factors for cortical cataracts is increased exposure to sunlight. A dose-dependent relationship between lifetime sunlight exposure and cortical cataract was convincingly demonstrated in a study of fishermen (Taylor et al., 1988; Taylor, 1989). This association has been confirmed in numerous epidemiologic studies, many of which were

reviewed recently (McCarty and Taylor, 2002). Since exposure can be controlled, emphasis has focused on modifying behavior to reduce ocular exposure to sunlight and other sources of ultraviolet radiation.

Although a causal connection between sunlight and cortical cataracts is apparent from epidemiologic studies, the mechanism underlying this increased risk is uncertain. The propensity for cortical cataracts to form in the inferior half of the lens, especially in the inferior nasal quadrant, has been suggested as evidence that light causes cortical cataracts, perhaps aided by peripheral focusing by the cornea (Coroneo et al., 1991; Merriam, 1996; Kwok et al., 2004). However, the earliest suture branches form in the inferior temporal quadrant and later branches are initiated in the inferior half of the lens, revealing an anatomic asymmetry that may also underlie this propensity (Kuszak et al., 2004). Unlike the effects of sunlight on the skin (Brash et al., 1991; Matsumura and Ananthaswamy, 2004), specific biochemical markers of sunlight exposure have not been detected in cortical cataracts. Exposure to UV light causes cataracts in animals (Soderberg, 1990; Zigman et al., 1991; Michael et al., 1998), but these animal studies have not provided critical insights about how sunlight contributes to human cataracts. UV-induced cataracts in animals generally do not resemble human cortical cataracts and most studies have been done on rodents, which are not adapted to sunlight exposure. The pupil is maximally constricted during sunlight exposure, limiting light access to the peripheral portions of the lens, where cortical cataracts originate. Dark iris color has been associated with cortical cataracts in some studies (Delcourt et al., 2000b; AREDS, 2001b), a finding that seems at odds with a direct effect of sunlight on the lens. Given the lack of evidence that sunlight directly damages the human lens in a way that contributes to cortical cataracts, consideration should be given to the possibility that sunlight exerts its cataractogenic effect on other parts of the eye, possibly the iris.

Toxic metabolites from the iris might reach the lens epithelium or cortex after being released into the posterior chamber (Andley et al., 1996).

In spite of the well-established connection between high sunlight exposure and cortical cataracts, the contribution of sunlight to cataracts is relatively small in the general population. For example, in a typical population in the US, individuals with the highest exposure to sunlight differed in their risk of cortical cataracts from those with the lowest exposure by only 10% (West et al., 1998). Similarly, in Australia approximately 10% of the risk of cortical cataracts was attributable to sunlight exposure. In this population, the risk from sunlight was lower than the risk associated with being female or having a family history of cataract (McCarty et al., 2000).

Therefore, even though sunlight is a well established, largely avoidable risk factor, epidemiologic data suggest that increased exposure to sunlight is unlikely to be involved in the formation of most cortical cataracts. Again referring to Koch’s postulates, (1) light is certainly present in the lens, although its specific, harmful biochemical effects have not been detected in cortical cataracts. (2) Increased sunlight increases the risk of cataracts in a dose-dependent manner. However, (3) it appears likely from epidemiologic data that markedly restricting exposure to sunlight will prevent only a modest fraction of cortical cataracts. To increase the chances of preventing or delaying cortical cataracts, increased emphasis should be placed on understanding the contributions of other known risk factors. These include (but are not limited to), genetic predisposition, gender-related variables and age-related changes in the lens.

I. Risk Factors for Cortical Cataracts:

Presbyopia

In humans, cortical cataracts typically begin as punctate areas of damage in the middle of small bundles of mature fiber cells (Brown et al., 1993). It has been suggested

that these defects could be generated during accommodation by mechanical shear stress between the hardening nucleus and the softer cortex (Pau, 2006). Continued mechanical stress could account for the progression of the opacity along the length of the affected fibers and the increasing involvement of adjacent groups of fibers.

While hardening of the lens nucleus correlates with the time of onset of cortical cataracts, this hypothesis provides little insight into why some individuals develop cortical cataracts and others do not. The lens nucleus hardens at a remarkably uniform rate (as measured by loss of accommodative amplitude) in essentially all individuals (Glasser and Campbell, 1998; Heron and Charman, 2004; Heys et al., 2004), yet only a fraction develop cortical opacities. Epidemiologic studies showing that larger lenses were at risk of nuclear cataracts also showed that individuals with smaller lenses were much more likely to develop cortical cataracts (Klein et al., 1998, 2000a). The importance of lens growth and hardening may be better evaluated once the genetic factors that contribute to a large fraction of cortical cataracts are identified (Hammond et al., 2001; Iyengar et al., 2004).

J. Risk Factors for Cortical Cataracts: Diabetes

It has long been recognized that diabetes is a risk factor for cataracts, especially cortical cataracts (Hodge et al., 1995). As a result, the induction of experimental diabetes in animal models has often been used to understand the etiology of diabetic cataracts and to test treatments that are intended to prevent diabetic complications in the lens and throughout the body. These animal studies have led investigators to favor several mechanisms to account for diabetic cortical cataracts, including osmotic damage to cortical fiber cells due to the accumulation of the glucose metabolite, sorbitol (Kinoshita, 1986), increased oxidative damage leading to opacification (Obrosova et al., 1999; Hegde and Varma,

2005) and increased glycation of lens proteins (Van Boekel, 1991), leading, directly or indirectly, to increased opacification.

There is reason to question the relevance of most animal models of diabetic cataract to the cataracts that occur most often in human diabetics. Individuals with poor or no control of blood glucose are at greatly increased risk of life-threatening complications, like heart disease, renal failure and stroke. For these patients, cataracts are unlikely to be the primary health consideration, even if cataracts are their initial complaint. Animal models most closely resemble patients with uncontrolled type I diabetes; young individuals with very high blood glucose and no restriction of carbohydrate consumption. The cataracts that occur under these conditions develop rapidly and are diffuse opacities that involve the entire lens cortex. However, as described below, these cataracts do not resemble the opacities seen most often in human patients. Treatments that prevent or delay the acute cataracts seen in animal models may be valuable in preventing other types of diabetic complications. Whether they will reduce the occurrence or severity of cataracts in diabetics with better glycemic control needs to be tested.

Most diabetics with access to good medical treatment have fair to good control of blood glucose levels, leading to fewer complications and greater longevity. The cataracts that develop in diabetics under these more common conditions closely resemble typical age-related cataracts, not the rapid onset, total cortical cataracts seen in animal models or in young patients with uncontrolled diabetes (Bron et al., 1993). Recent epidemiologic studies confirm that, although cortical cataracts often occur in diabetics, PS cataracts, and even nuclear cataracts, are also common in these patients. For example, in three recent studies there was a similar risk of diabetics having PS or cortical cataracts (Delcourt et al., 2000b; Hennis et al., 2004; Congdon et al., 2005), while in another, cortical, nuclear and PS cataracts were found in similar numbers (Tung et al., 2005). In one population-based

study, diabetes was an independent risk factor for PS, but not cortical cataracts (Mukesh et al., 2006). The perception in the lens research community that diabetes is linked exclusively with cortical cataracts contrasts with evidence that, in human patients, PS cataracts are an equally common complication of this disease. Given that PS cataracts occur less frequently in most populations, their increased prevalence in diabetics suggests that diabetes has a greater differential effect on the formation of PS cataracts than on cortical cataracts. These observations suggest that further studies of the mechanisms underlying the formation of PS cataracts, especially in diabetics, are warranted.

K. Risk Factors for PS Cataracts: Steroid Exposure

Long-term or high dose exposure to steroids has long been known to increase the risk of PS cataracts (reviewed in Jobling and Augusteyn, 2002). As mentioned above, the recent increase in the use of intravitreal steroids in ophthalmic practice will lead to a corresponding increase in PS cataracts. In spite of the awareness of this complication, the benefits of steroid use outweigh the risk of cataract formation. Better understanding of the mechanisms by which steroids produce PS cataracts could lead to approaches that spare the lens. However, there have been few animal models that resemble human steroid-induced PS cataracts (Jobling and Augusteyn, 2002).

A recent study showed that exposure of cultured rat lenses to high dose glucocorticoids rapidly induced pathology that resembled human PS cataracts (Lyu et al., 2003). Cataract formation was prevented by co-administration of a glucocorticoid receptor antagonist and was associated with decreased levels of the cell adhesion proteins, N- and E-cadherin. Since N-cadherin is abundant at the apical adherens junctions and along the lateral membranes of elongating fiber cells (Beebe et al., 2001), decreased expression of this protein could

be involved in the failure of lens fiber cell elongation leading to PS cataract formation. Identification of the mechanisms by which cell adhesion molecules are selectively regulated in the lens by glucocorticoid treatment is a promising avenue for further study. It would be interesting to validate this model by comparing the results of this study with lens material obtained from human steroidinduced cataracts.

L. Risk Factors for PS Cataracts: Ionizing Radiation

Following the observation that atomic bomb survivors were at increased risk of cataracts (Minamoto et al., 2004), it was recognized that therapeutic X- or gammairradiation increases the risk of PS cataracts (Cogan et al., 1952; IARC, 2000). Lower dose exposures, as in diagnostic X-rays, appear to carry little risk of cataract formation (Hourihan et al., 1999; Klein et al., 2000b). Radiation cataracts have been studied extensively in animal models (Worgul et al., 1976). Although most radiation-induced cataracts in animals are cortical, the results of these studies seem likely to apply to human PS cataracts. The most relevant aspects of these studies are that the dividing cells in the germinative zone of the lens epithelium appear to be the critical target of radiation damage. Shielding these cells or inhibiting lens cell proliferation prevents cataract formation, even after very high doses of X-rays (Alter and Leinfelder, 1953; Holsclaw et al., 1994). It is striking that we do not yet know the series of events by which damage to dividing epithelial cells is translated into a cortical or PS opacity weeks or months after the injury.

VII. FINAL THOUGHTS

A great deal is known about the development, function and aging of the normal lens. However, as pointed out in this chapter, basic understanding is lacking about a

few key issues. These include the nature and cause of the barrier to diffusion that develops during aging, and the events that lead to the age-related hardening of the lens. We also have a basic understanding of the nature of age-related cataracts and extensive information about risk factors for these pathologies. Major issues in cataract research that remain to be addressed include an explanation for the increased risk of cataracts in women, identification of the genes and pathways that underlie the increased hereditary risk of nuclear and cortical cataracts, and strategies to inhibit the formation of PS cataracts in diabetics and during steroid and radiation therapy. Translation of our knowledge of lens function and cataract formation in animal models to the function and pathology of the human lens is needed now more than ever. Developing effective strategies to prevent or slow age-related cataracts will require partnerships between clinicians and basic scientists and the willingness of the ocular pharmaceutical industry to respond to opportunities when they arise.

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