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| November 2003 | Inside IOVS | Volume 44/11 |
A Gene Mutation in Herpes Simplex Enhances Ability to Cause Keratitis
Herpes simplex virus keratitis is an important cause of blindness despite the availability of antiviral drugs. Improved understanding of virulence could lead to improved treatments. HSV-1 contains several virulence genes, and one, US1, encodes a heavily modified pleiotropic immediate early protein existing in several isoforms. Previously, the US1 gene from strain OD4 was shown to contain a mutation Y116C. Brandt and Kolb (p. 4601) reversed the mutation, thereby restoring keratitis, indicating that Y116 is required for virulence. Analysis revealed that the OD4 a22 isoforms and tryptic phosphopeptide patterns differed from wild-type strain CJ394. These results show a connection between post-translational modification and capacity of HSV-1 to cause keratitis.
Control of Fibulin-3 Expression in the Retina
New components of the retinal extracellular matrix are emerging. One of these, fibulin-3, has recently been linked to the disease 'dominant drusen' (Malattia Leventinese, Doyne's honeycomb retinal dystrophy). This study by Blackburn et al. (p. 4613) looked at the transcriptional control of the gene encoding fibulin-3, in vitro and in cells derived from the retinal pigment epithelium, the likely target in 'dominant drusen'. A number of regulatory elements were found, in particular an estrogen response element. Cell studies show that estrogen down-regulates the expression of fibulin-3, highlighting a novel role for circulating estrogen in the retina and also in the pathogenesis of retinal drusen.
Heparin II Domain of Fibronectin Increases Outflow Facility
Santas et al. (p. 4796) report that recombinant heparin II domains of fibronectin increased outflow facility in cultured human anterior segments. The increase in facility was associated with the disruption of canal cells along the inner and outer wall of Schlemm's canal. These disruptions alone could not account for the increase in facility, since facility returned to baseline once the domain was removed. This study demonstrates that specific matrix proteins have a role in modulating aqueous hydrodynamics and suggests possible physiological mechanisms that may control outflow facility. Therapeutic modalities directed at these proteins may represent possible approaches to the treatment of glaucoma.
Smoking Reduces Choroidal Vascular Reactivity in Human Subjects
Smoking is a risk factor for many eye diseases. Wimpissinger et al. (p. 4859) have compared the regulatory capacity of the human choroid in response to isometric exercise-induced changes in ocular perfusion pressure in smokers and non-smokers. The results show that choroidal blood flow is less well regulated in smokers as compared to age-matched controls. These data indicate abnormal choroidal blood flow regulation in chronic smokers, which may be related to the risk of developing ocular vascular disease and age-related macular degeneration.
Bone Marrow Progenitor Cells in CNV
Choroidal neovascularization (CNV) pathogenesis is postulated to be driven by angiogenesis in which the cellular components of the new vessels are derived from the adjacent choriocapillaris. Espinosa-Heidmann et al. (p. 4914) report that bone marrow-derived progenitor cells are a source of endothelial and smooth muscle-like cells in CNV. Bone marrow-derived progenitor cells may promote regeneration of damaged vessels but may also contribute to pathological responses.
Integration between Abutting Retinas
Reconstruction of degenerated retinas by subretinal transplantation of retinal tissue is limited by poor graft-host integration. Prompted by this problem, Zhang et al. (p. 4936) developed a modified retinal organ culture system. The system consists of abutting retinal pieces placed side-by-side or overlapping each other (simulating the in vivo situation of subretinal transplantation). The study provides evidence that while extensive bridging of neuronal fibers can occur between two retinas when they are placed side-by-side, integration is limited when they overlap each other. The system proved useful in simulating the in vivo situation and can be used to examine the factors limiting integration and how it may be influenced.
Light Adaptation-Mediated Photoreceptor Protection
Animals raised in relatively bright environments are protected against light-induced photoreceptor degeneration, compared to rats raised in dim cyclic light or darkness. This adaptability encompasses many aspects of retinal cell and molecular biology and physiology. Li et al. (p. 4968) demonstrated that adaptation to 400-lux bright cyclic light for 4 days significantly reduced photoreceptor apoptosis induced by constant light damage, which correlated with a significant increase in bFGF expression. This indicates that the retina of the adult rat can rapidly up-regulate neuroprotective mechanisms when switched from dim to bright cyclic light. Identification of the molecules involved in this process may allow rational development of therapeutic approaches to treat retinal degenerative diseases.
Sustained Transcleral Delivery of a Kinase Inhibitor Suppresses CNV
Sustained local delivery of medications to the eye has the potential advantage of minimizing systemic side-effects. Saishin et al. (p. 4989) provide proof of concept for sustained transcleral delivery of a small molecule inhibitor in a pig model of CNV. Oral administration of PKC412, a kinase inhibitor that blocks the receptors for VEGF, PDGF, stem cell factor, and several isoforms of PKC, has previously been shown to inhibit retinal and choroidal NV in mouse models. Periocular injection of microspheres loaded with PKC412 resulted in high intraocular levels and suppression of CNV at Bruch's membrane rupture sites in pigs. This suggests that sustained transcleral delivery of anti-angiogenic drugs should be considered for treatment of ocular neovascularization in humans.
Topical D-b-Hydroxybutyrate Is Beneficial in a Model of Dry Eye
D-b-hydroxybutyrate (HBA) has been shown to ameliorate tissue damage, protein catabolism, and metabolic dysfunction in various stressful conditions. However, the effects of HBA on ocular surface epithelial disorders have not been investigated. Nakamura et al. (p. 4682) have demonstrated that topically applied HBA is beneficial for corneal epithelial erosions due to ocular surface desiccation. Application of HBA suppresses induction of apoptosis induction in an experimental model of dry eye in rats. These findings suggest the potential usefulness of HBA in the clinical treatment of ocular surface epithelial disorder in patients with dry eye.
The Maturity of Specific T Lymphocyte Populations Affects Chronicity in Uveitis
Experimental autoimmune uveitis (EAU) in mice is a model for human uveitis, a blinding disease mediated by T lymphocytes specific to retinal antigens. Uveitis occurs despite presence in the eye of transforming growth factor beta (TGF-b), a known inhibitor of inflammation and an important player in ocular immune privilege. Xu et al. (p. 4805) found that recently generated effector/memory T lymphocytes, capable of causing uveitis, are sensitive to inhibition by TGF-b. In contrast, mature uveitogenic effector/memory T cells are refractory to the effects of this cytokine. If equivalents of such cells exist in chronic uveitis patients, they may help to explain persistence of inflammation in the face of the high levels of TGF-b present in ocular fluids.
Lens Epithelial Cell Proteome
Due to the difficulty in obtaining human lens epithelial cells from donors, immortalized cultured cells are often used to study lens biology. However, few studies have compared the protein composition of freshly isolated lens epithelial cells to cultured cells. Su et al. (p. 4829) identified the major proteins present in human lens epithelial cells and suggests that immortalized cells undergo dramatic changes in the composition of their major proteins. While establishment of lens epithelial cell lines is necessary to study many aspects of lens biology, these results indicate that caution should be used when generalizing results obtained from cultured cells.
Lomerizine and Optic Nerve Head Circulation
A beneficial effect of oral calcium antagonists has been reported on glaucomatous visual-field damage. Tamaki et al. (p. 4864) investigated the effects of lomerizine, a Ca2+ antagonist, on the ocular tissue circulation in rabbits and on the circulation in the optic nerve head (ONH) and choroid in healthy volunteers. Lomerizine increases blood velocity, and probably blood flow, in the ONH and retina in rabbits, and it also increases blood velocity in the ONH in healthy humans without significantly altering blood pressure or heart rate. Lomerizine might have clinical potential for conditions complicated by ocular circulatory disturbances in the retina or ONH.
Retinal Pigment Epithelium is a Source for Endothelin-1
Retinal pigment epithelial (RPE) cells synthesize and release endothelin-1 (ET-1) under basal and stimulated conditions, depending on the age in culture. Narayan et al. (p. 4885) showed that tumor necrosis factor alpha (TNFa) produces a time-dependent release of ET-1 that corresponds with the disassembly of tight junctions, reminiscent of a compromised blood-retinal barrier. Stimulation of muscarinic cholinergic receptors (M1 & M3) was effective in releasing ET-1 from RPE only in young cultures without alterations in the integrity of tight junctions. It is proposed that in diseased conditions that result in a breakdown of the blood-retinal barrier, ET-1 released by RPE may be important for critical repair mechanisms, including cell migration and proliferation.
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