Iron, the retina and the lens: a focused review.

This review is focused on iron metabolism in the retina and in the lens and its relation to their respective age-related pathologies, macular degeneration (AMD) and cataract (ARC). Several aspects of iron homeostasis are considered first in the retina and second in the lens, paying particular attention to the transport of iron through the blood-retinal barrier and through the lens epithelial cell barrier, to the immunochemistry of iron-related proteins and their expression in both the retina and the lens, and to the nature of the photochemical damage caused by UV light on both tissues. A comparative overview of some iron related parameters (total iron, transferrin (Tf), transferrin saturation and total iron binding capacity), in plasma and ocular tissues and fluids of three animal species is also presented. Based on results selected from the literature reviewed, and our own results, a scheme for the overall circulation of iron within and out of the eye is proposed, in which, (i) iron is pumped from the retina to the vitreous body by a ferroportin/ferroxidase-mediated process at the endfeet of Müller cells, (ii) vitreal Tf binds this iron and the complex diffuses towards the lens, (iii) the iron/Tf complex is incorporated into the lens extracellular space probably at the lens equator and moves to the epithelial-fiber interface, (iv) upon interaction with Tf receptors of the apical pole of lens epithelial cells, the iron/Tf complex is endocytosed and iron is exported as Fe(3+) by a ferroportin/ferroxidase-mediated process taking place at the basal pole of the epithelial cells, and (v) Fe(3+) is bound to aqueous humor Tf and drained with the aqueous humor into systemic blood circulation for recycling. The proposed scheme represents an example of close cooperation between the retina and the lens to maintain a constant flow of iron within the eye that provides an adequate supply of iron to ocular tissues and secures the systemic recycling of this element. It does not discount the existence of additional ways for iron to leave the eye through the blood-retinal barrier. In this review both AMD and ARC are recognized as multifactorial diseases with an important photoxidative component, and exhibiting a remarkable similitude of altered local iron metabolism. The epidemiological relationship between ARC and ferropenic anemia is explained on the basis that hepcidin, the hormone responsible for the anemia of chronic inflammation, could paradoxically cause intracellular iron overload in the lens by interfering with the proposed ferroportin/ferroxidase-mediated export of iron at the basal side of the anterior lens epithelium. Other authors have suggested that a similar situation is created in the retina in the case of AMD.

A comparative study of iron-related metabolic parameters in the eye of three animal species.

In order to obtain a wider perspective of iron homeostasis in the eye, a comparative study was undertaken of several iron-related parameters (Total Iron, TI; Total Iron Binding Capacity, TIBC; Transferrin, Tf; and saturation of Tf) both in blood serum and in ocular tissues (lens, cornea, iris-ciliary body, retina) and fluids (vitreous body, aqueous humor) of several animal species (pig, cow and rat). The relative degree of oxidative stress of tissues and fluids was evaluated based on the criteria that high values of TI and Tf saturation, and low values of TIBC and Tf, would promote iron-related oxidative stress. The inclusion of both diurnal (pig, cow) and nocturnal (rat) animal species in this comparative work provided the opportunity to explore if iron homeostasis parameters are in some way influenced by the higher oxidative stress level expected in animals with diurnal living habits. This project involved also the design of new and very sensitive methods of analyses, given the fact that in many cases very small amounts of sample (i.e., aqueous humor), and/or low concentration of analytes (i.e., transferrin) are available. All results were expressed as concentration relative to mg protein as determined with the Bradford method (microplate assay). When analyzing TI/TIBC it was possible to define a loosely bound iron pool (LBIP) in ocular tissues that was proportional to the degree of vascularization of the tissues analyzed. The comparison of iron related parameters patterns within the eye and among species allowed us to reach the following conclusions: (1) The aqueous humor and vitreous body of cow and pig exhibited highest concentration of Tf and a very low saturation of Tf, while the lowest value of Tf was detected in all species in the lens; (2) TI showed the tendency to be highest in the vitreous body of cow and pig, and lowest in the lens of all three species. The very low iron concentration in the lens may effectively counteract the risk of having a low Tf level; (3) The pattern of distribution of TIBC is the same for the cow and the pig; (4) Saturation of Tf was very high in the rat aqueous, also high in the rat lens and serum; (5) Highest differences in the pattern of distribution of iron parameters in the eye among the three species studied were found between the rat and the other two species, suggesting that the nocturnal habit of living is influencing iron related parameters in the rat. Lacking the full effect of UV light on the eye, the rat apparently lives exposed to high risk iron parameters without overt pathology, but its antioxidant reserves must be minimal. For example, the combination of high TI aqueous with relatively low Tf, gives a dangerous high saturation of Tf (82%) in the rat; (6) The posterior part of the lens is exposed to high levels of iron and Tf in diurnal animals, with saturation of Tf in the vitreous in the 40% level. This could facilitate postvitrectomy cataracts in addition to the documented increase in vitreous level of oxygen under those conditions.

Diabetes can alter the signal transduction pathways in the lens of rats.

Diabetes is known to affect cataract formation by means of osmotic stress induced by activated aldose reductase in the sorbitol pathway. In addition, alterations in the bioavailability of numerous extralenticular growth factors has been reported and shown to result in various consequences. We have found that the basic fibroblast growth factor (bFGF) accumulates in the vitreous humor of 3- and 8-week diabetic rats. Consequently, the associating signal transduction cascades were severely disrupted, including upregulated phosphorylation of extracellular signal-regulated kinase (ERK) and the common stress-associated mitogen-activated protein kinases p38 and SAPK/JNK. Conversely, under diabetic condition, we observed a dramatic inhibition of phosphatidylinositol-3 kinase activity in lenses obtained from the same animal. Rats treated with the aldose reductase inhibitor AL01576 for the duration of the diabetic condition showed that the diabetes-induced lenticular signaling alterations were normalized, comparable to controls. However, treatment of AL01576 in vitro was ineffective at normalizing the altered constituents in extracted diabetic vitreous after the onset of diabetes. The effect of AL01576 in the high galactose-induced cataract model in vitro was also examined. Administration of AL01576 to lens organ culture normalized the aberrant signaling effects and morphological characteristics associated with in vitro sugar cataract formation. In conclusion, our findings demonstrate diabetes-associated alterations in the lens signal transduction parameters and the effectiveness of AL01576 at normalizing such alterations. The causes for these alterations can be attributed to elevated vitreal bFGF in conjunction with osmotic stress and associated attenuation in redox status of the lens.

Peróxido de hidrógeno en el humor acuoso: 1992-1997 / Hydrogen peroxide in the aqueous humor: 1992-1997

Ideas prevailing in 1991 on hydrogen peroxide in the aqueous humor are outlined. They are critically examined under the light of our finding that the method used to establish aqueous humor levels of peroxide generates itself peroxide during the short time span of the analysis. This is due to the fact that the probe used, dichlorophenol indophenol (DCPIP), spontaneously auto-oxidizes in the presence of oxygen. It was concluded then that the level of hydrogen peroxide in the aqueous humor cannot be higher than about 0.3 microM, the detection limit of the DCPIP method. It was also concluded that the statement commonly made in the literature that aqueous humor hydrogen peroxide derives from the oxidation of ascorbate, an abundant component of that fluid, is based solely on the use of the DCPIP method, and so could easily be due to a methodological artifact. The same applies to the statement that the levels of hydrogen peroxide are very high in human senile cataracts. The surprising resistance to accept the results and conclusions of our 1992 publication is documented. Finally, the content is discussed of an oral presentation made at the 1997 ARVO Annual Meeting in which an important portion of our results and conclusions was confirmed, perhaps signaling a shift towards a wider acceptance of our findings.

Antibodies to lens crystallins after endocapsular cataract surgery

Levels of serum antibodies against lens alpha, beta H and beta L crystallins were determined in 15 patients before and after endocapsular cataract extraction. The most abundant antibody at the time of surgery was anti-beta L, followed by anti-beta H and anti-alpha. An increase in the basal levels of these antibodies was seen after surgery in 93 percent of the cases. Relative increase was highest for anti-alpha, followed by anti-beta H and anti-beta L. There were individual variations both in the shape of the time-dependent antibody response after surgery and in the relative intensity of the response to the different antigens. The endocapsular technique therefore leads to the release of crystallins into the anterior chamber in sufficient amounts to provoke in many patients a humoral immune response

Melanins and lens pigments: a comparative study

Based on previous findings that lens pigments and melanins share many physicochemical properties, human lens pigments and natural (hair) and synthetic melanins were submitted to oxidation with permanganate under strong acidic conditions. This procedure has been utilized for the characterization of melanins and results in the well defined products, thiazole-4,5-dicarboxylic acid (TDCA) and pyrrole-2,3,5-tricarboxylic acid (PTCA), which can be quantitated by high performance liquid chromatography (HPLC). PTCA is regarded as a marker of black eumelanins and was therefore a main component of synthetic DOPA-eumelanin and dark hair. Its identity was established by synthesis from 5-hydroxyindole-2-carboxylic acid. TDCA derives from pheomelanins and was therefore an important component of red hair and synthetic GSH-pheomelanin. TDCA was identified by its retention time relative to PTCA. The analysis of a series of cataract digests of increasing pigmentation (type I < type IV < type V) and a purified fraction of lens pigments (DE52 pigment) revealed the presence in these preparations of both PTCA and TDCA. The concentration of TDCA significantly increased with the degree of pigmentation of the digests and reached a maximum in the DE52 pigment. The TDCA/PTCA ratio was high in the lens preparations and comparable to that given by hair pheomelanin. These findings support that pheomelanin is an integral part of lens pigments. By comparing the yields of TDCA in GSH-pheomelanin and in the purified lens pigment, a 9 per cent contribution of pheomelanin to the lens pigment was estimated

Computer eyestrain

Se discuten en este trabajo los mecanismos oculares probablemente mas importantes de los síntomas de astenipia en usuarios de computadoras: reducción del volumen de la secreción lacrimal, fatiga de los músculos extraoculares, fatiga al color y reducción de la amplitud de acomodación inducida por la luz monocromática. Sobre esta base se derivan algunas reglas prácticas para evitar o reducir la astenopia

Environmental protection of the human lens

Se determinó la efectividad de los siguientes lentes: cristal verde 3, cristal gris 3, cristal claro, cristal photogray, cristal Revo anaranjado solar, cristal Revo azul ariel, plástico claro, plástico U-V Gard y plástico U-V Gard gris en evitar el aumento en temperatura al iluminarla con una lámpara de tungsteno. El lente más efectivo en evitar el aumento en temperatura fue el cristal verde 3 seguido por el cristal gris 3 y los cristales Revo azul anaranjado. Estos se recomiendan para proteger los ojos del desarrollo prematuro de la presbicie el aumento en temperatura

Retinal stimuli in ocular accommodation

Se determinó la amplitud monocular de acomodación en 22 ojos de pacientes entre los 18 y 34 años de edad usando iluminación de bombillas de tugsteno de 40 y 75 vatios. También se obtuvieron amplitudes usando filtros verde, rojo y azul. La luz policromática, proveniente especialmente de la bombilla de 75 vatios, produjo las amplitudes de acomodación mayores. En orden descendente la luz verde estimuló un grado mayor de amplitud que la roja y la roja más que la azul. Los resultados del estudio demostraron que la aberración cromática, la iluminación y el contraste son los factores más importantes en estimular retinalmente la acomodación ocular

In vivo transfer of ascorbate and dehydroascorbate to the aqueous humor of the eye in the domestic cat and the rhesus monkey

Se ha estudiado in vivo, en gatos domésticos y en macacos thesus, la incorporación de ascorbato y dehidroascorbato (DHA) al humor acuoso.l En el gato se encontró que los niveles de ayunas de ascorbato en el humor acuoso (1.49 mg%) se mantienen unas 6 veces por encima de los séricos, lo cual se ha tomado como undcación de la existencia de un proceso de transporte activo para ascorbato en el cuerpo ciliar de este animal. También se ha determinado que la transferencia de ascorbato al humor acuoso en el gato tiene dos componentes, uno saturable, mediado, con parámetros cinéticos Tm = 4.9 mg% y Kt = 0,53 mg%, que debe ser responsable del transporte activo, y otro que nos es saturable, sino tipo difusión sencilla. En el mono se detectó un sistema de transporte mediado, sin componente difusivo, con Tm = 22.6 mg% y Kt = 0.28mg%, y capaz de mantener en el humor acuoso una concentración de ascorbato 25 veces mayor que en el plasma. Los valores de ayunas de ascorbato en el suero del mono (0.69 mg%) se mantienen sobre el suero del mono (0.69 mg%) se mantienen sobre el nivel de saturación del sistema de transporte, a diferencia de lo que ocurre en el gato. DHA no pudo detectarse en el plasma del gato ni del mono, ni en el humor acuoso del gato. Sí pudo detectarse, sin embargo, en el humor acuoso del mono, a niveles de un 3% de la concentración de ascorbato total. La cinética de la incorporación de ascorbato al ojo del gato y del mono tras la inyección intravenosa de DHA apoya la idea de que la especie molecular que el cuerpo ciliar transporta es la forma reducida, ascorbato, y no DHA. Este sería convertido intravascularmente (leucocitos y hematíes) a ascorbato, antes de incorporarse al humor acuoso

Sobre las influencias ambientales relevantes a la prevencion del desarrollo precoz de la catarata senil. / On relevant environmental effects on the prevention of early development of senile cataract

Los autores presentan la hipotesis de que el factor geografico detectable en la epidemiologia de presbicie y catarata senil depende de efectos ambientales sobre la temperatura del cristalino. El efecto de la luz ultravioleta de la radiacion solar parece ser de menos importancia en precipitar cambios senescentes en el cristalino. Se ha llegado a esta conclusion por medio del analisis de datos epidemiologicos sobre el comienzo de la presbicie y prevalencia de la catarata senil en paises con diferentes climas y en diferentes altitudes dentro del mismo pais. Desde el puento de vista preventivo, por tanto, parece ser mas importante en climas calidos evitar que la temperatura del cristalino suba que evitar que la luz ultravioleta de la radiacion solar penetre en el ojo