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| April 2004 | Inside IOVS | Volume 45/4 |
The Incredible Shrinking Optic Nerve
Karim et al. (p. 1047) compare magnetic resonance imaging (MRI) measurements with histologic measurements of the intraorbital optic nerve in living and cadaveric humans. Their findings confirm a significant decrease in intraorbital optic nerve diameter from anterior to posterior in normal humans. They find that it is a decrease in collagen, rather than precious axons, that is responsible for the tapering of the optic nerve. Quantitative high resolution MRI, which is capable of detecting subtle size changes, might be useful in investigation of congenital and acquired optic neuropathies.
Lipofuscin in Human RPE Becomes More Photoreactive with Aging
Lipofuscin is an age-pigment which accumulates in a variety of tissues and has been implicated in several disease processes including photodamage to the eye and age-related macular degeneration. Różanowska et al. (p. 1052) demonstrate that human retinal pigment epithelium (RPE) lipofuscin granules become more photoreactive with aging. The age-related increase in lipofuscin photoreactivity is due to the age-related increase in the content of chloroform insoluble components. Therefore, the increased risk of photo-oxidative damage to RPE with aging is related not only to the increased number of lipofuscin granules but also to the increased photo-induced reactivity of the average granule.
Insulin Signaling and Wound Healing of Corneal Epithelium
Diabetes is often associated with delayed wound healing and impaired corneal re-epithelialization. The underlying cellular and signaling mechanisms have yet to be determined. Shanley et al. (p. 1088) report that insulin accelerates monolayer wound healing of human corneal epithelial cells in vitro, which is mediated via Phosphoinositide 3-kinase (PI3 kinase) and extracellular signal regulated kinase (ERK 1/2). These data suggest a mechanism by which insulin may influence corneal wound healing in vitro. In vivo, disruptions to the insulin signaling pathway observed in diseases such as diabetes might account for the delayed wound healing and corneal defects. Insulin and the ensuing signaling may be potential management targets.
Thymosin beta 4 (Tβ4) Inhibits Corneal Epithelial Cell Apoptosis In Vitro
Sosne et al. (p. 1095) describe a possible mechanism by which Tβ4, a recently identified wound healing agent, may prevent corneal epithelial cell apoptosis, thereby optimizing outcomes of corneal ablation procedures such as LASEK. Cells treated with Tβ4 and ethanol compared to those treated with ethanol alone exhibited decreased mitochondrial membrane alterations and release of cytochrome c, enhanced Bcl-2 expression and suppressed caspase activity. These results suggest novel mechanisms of action of Tβ4 in the cornea and augment the growing literature on the wound healing properties of Tβ4.
Pax6 and Corneal Function
Collinson et al. (p. 1101) have investigated corneal function in the Pax6+/- mouse model of aniridia-related keratopathy. They find that centripetal migration of corneal epithelial cells is severely disrupted in Pax6+/- mice, and that fewer clones of limbal stem cells can be detected. Analysis of Pax6+/- ↔ Pax6+/+ chimeras suggests that Pax6+/- corneal epithelial defects may in part be a secondary consequence of a failure of other tissues, such as the lens, to correctly organize anterior segment development. This implies that putative genetic therapies for aniridia-related keratopathy may need to target both corneal and non-corneal ocular tissues.
Role of the C Domain of IGFs in Corneal Epithelial Wound Healing
Yamada et al. (p. 1125) show that the C domain of insulin-like growth factors (IGFs) -1 or -2 is responsible for the synergistic promotion of corneal epithelial migration in vitro induced by these growth factors and the sensory neurotransmitter substance P. A biological function of the C domain of IGFs has not previously been described. Furthermore, treatment of rabbits with eyedrops containing peptides corresponding to the C domain of IGF-1 and to the carboxyl terminus of substance P significantly promoted the closure of corneal epithelial wounds, providing the basis for development of a new peptide-based strategy for the treatment of corneal wounds in humans.
MIF in Ocular Cicatricial Pemphigoid
Macrophage migration inhibitory factor (MIF) plays an important role in determining the inflammatory phenotypes in the injured organs, by inhibiting the migration of macrophages from the affected sites. Razzaque et al. (p. 1174) found that an increased conjunctival accumulation of macrophages was associated with an increased conjunctival expression of MIF, in patients with ocular cicatricial pemphigoid (OCP). This study provides information that may lead to a comprehensive understanding of the conjunctival inflammatory process. Determining the molecular mechanisms of the conjunctival accumulation of inflammatory cells will help to define their specific functions in the disease process, and will also help in developing novel therapeutic strategies to treat patients with OCP.
Corneal Graft Rejection and Interferon-gamma
Corneal graft rejection is associated with activation of Th1 lymphocytes that secrete interferon-gamma (IFN-γ). Hargrave et al. (p. 1188) found that, although 50-77% of MHC-matched corneal grafts were rejected in normal hosts, none of the grafts were rejected in 57 IFN-γ knockout mice, and only one graft was rejected in 10 normal mice treated with anti-IFN-γ antibody. The results indicate that MHC matching dramatically reduces the risk of corneal graft rejection in hosts who have compromised Th1 immune responses and possibly in hosts, such as those with severe atopy, whose immune phenotype is tilted strongly in the Th2 direction.
Corneal Angiogenic Privilege Is Actively Maintained
The normal cornea is free of both blood and lymphatic vessels. Avascularity is essential for corneal transparency and visual acuity. Whereas the cornea has been used as the in vivo model to study angiogenesis, the mechanisms maintaining corneal avascularity are poorly understood. Cursiefen et al. (p. 1117) demonstrate that thrombospondin (TSP) 1 and 2 are essential endogenous inhibitors of inflammatory corneal angiogenesis in the murine cornea. In contrast, genetic deletion of TSP 1 or 2 did not cause spontaneous developmental corneal angiogenesis. This not only suggests an active maintenance of corneal avascularity by several antiangiogenic factors, but also the potential to use TSP 1 and 2 to prevent corneal angiogenesis.
Susceptibility of Retinal Vascular Endothelium to T. gondii Infection
Retinochoroidal infection with the protozoan parasite, Toxoplasma gondii, is the most common cause of posterior uveitis worldwide. Smith et al. (p. 1157) studied the susceptibility of human retinal microvascular endothelium to infection with actively dividing T. gondii tachyzoites, in comparison to other vascular endothelial cell subtypes. Their experiments demonstrated a relatively high susceptibility of cultured retinal vascular endothelium to T. gondii infection. If tissue specificity of T. gondii infection is dependent, in part, on a selective interaction with the retinal microvasculature, targeted therapies that are directed toward this interaction may offer a new treatment option for toxoplasmic retinochoroiditis.
Up-Regulation of Retinal GFRa-2 after Light Damage
Jomary et al. (p. 1240) have studied the retinal expression of selected members of the GDNF family ligands and their receptors in a rat model of photoreceptor apoptosis induced by exposure to intense light. They found that expression of these genes is independently regulated and that neurturin receptor was strikingly up-regulated. Since upregulation of neurturin, but not its receptor, is associated with photoreceptor apoptosis in a mouse model of inherited retinal degeneration, it could be postulated that the pattern of modulation of these genes during photoreceptor degeneration is determined by the nature of the apoptotic trigger and may reflect influences of the neurotrophic system on photoreceptor survival.
Metabolic Requirements of Cultured Rat RPE Cells
Wood et al. (p. 1272) show that rat RPE cells are primarily dependent upon a supply of glucose for maintenance of viability in culture. Such cells alternatively metabolize amino acids such as glutamine in the absence of glucose, but also have the ability to utilize monocarboxylates such as lactate or pyruvate to meet metabolic energy demands. These results have important implications for determining the susceptibility of RPE cells to insults such as anoxia, hypoglycemia, or ischemia, in situ. The relative susceptibility of different retinal cell-types to such metabolic insults is consequently discussed in relation to the reported findings.
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