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| May 2003 | Inside IOVS | Volume 44/5 |
Basal Retinovitreous Adhesion
At birth, the vitreous base is a band of firm adhesion between the vitreous gel and the posterior pars plana up to the ora serrata. However, throughout life, the posterior border of this band extends progressively into the peripheral neuroretina. The progression is caused by the de-novo synthesis of vitreous collagen by the retina, and the adhesion is formed by this collagen breaking through the inner limiting lamina and intertwining with pre-existing collagen within the vitreous cavity. As reported by Wang et al. (p. 1793), this work raises intriguing questions as to which retinal cells secrete the collagen and why the band of collagen synthesis gradually extends posteriorly.
Novel High Myopia Genetic Locus
There is substantive evidence that genetic factors play a significant role in the development of non-syndromic high myopia. As reported by Paluru et al. (p. 1830), three autosomal dominant (AD) loci for high myopia have been mapped to chromosomes 18p11.31, 12q23.1-q24, and 7q36 by linkage analysis. Linkage analysis of a large, multigenerational family with AD non-syndromic high myopia has uncovered a novel locus on chromosome 17q21-q22. The identification of implicated genes for myopia susceptibility may provide a fundamental molecular understanding of how myopia occurs, and may also identify pathways that are involved in eye growth and development.
Angiostatic Fusion Gene and Corneal Transplantation
Neovascularization of the corneal bed after penetrating keratoplasty frequently presages graft rejection and failure. The ex vivo transformation of donor tissue with expressible angiostatic genes could prove useful to the prolongation of graft survival. Endostatin XVIII and the Kringle 5 domain of Plasminogen have both been shown to inhibit endothelial cell proliferation and migration involved in angiogenesis. Murthy et al. (p. 1837) demonstrate prolonged survival of corneal grafts exposed to lentiviral vectors harboring a fusion gene encoding functional domains from these proteins. The ex vivo transduction of corneal tissue with anti-angiogenic genes, prior to transplantation, may substantially reduce the incidence of transplant failure.
Stress Protein Induction Protects Retinal Ganglion Cells in Rat Glaucoma
The hallmark of glaucomatous optic nerve damage is the loss of retinal ganglion cells. Ishii et al. (p. 1982) examined the effect of geranylgeranylacetone (GGA), a heat shock protein inducer that is clinically used to treat gastric ulcers, on the survival of retinal ganglion cells in an experimental model of glaucoma in rats. GGA induces heat shock protein-72 in retinal ganglion cells and protects them from death associated with intraocular pressure elevation. The findings suggest a novel neuroprotective pathway for the treatment of glaucoma.
Immunohistology of Cells in the Living Eye
Intrinsic to inflammation is the migration and interaction of a heterogeneous collection of leukocytes that can be differentiated by their cell surface phenotype. Traditional immunohistology of tissues ex vivo is a valuable technique for getting a snapshot of the cells present at any one time but does not allow serial studies of the exact same cells or tissues. Becker et al. (p. 2004) describe a method for in vivo immunohistology wherein fluorescently labeled antibodies or ovalbumin injected into an eye label specific cell types that can then be monitored in the living eye by intravital microscopy. This is a powerful method that will not only assist studies of inflammation and immunology, but also may potentially clarify other processes that evolve over time such as wound healing and apoptosis.
Matrix Metalloproteinases and Keratitis
MMPs play a major role in the cornea. Xue et al. (p. 2020) demonstrate that during pseudomonal keratitis IL-1b regulates the expression of MMP-9 in the cornea, and that reducing the levels of MMP-9 or IL-1b markedly reduced the extent of corneal damage. Therapies for bacterial keratitis that specifically target MMP-9 activation may provide an ideal way of controlling the scar-response that is the major cause of loss of sight during keratitis.
Gap Junction Proteins Promote the Differentiation of Lens Cells
Gap junctions formed by connexins are known to be important for maintaining metabolic homeostasis of the ocular lens. Gu et al. (p. 2103) report a novel functional aspect of a lens gap junction protein, connexin 45.6. The authors found that overexpression of connexin 45.6 in cultured lens cells stimulated cell differentiation, which converted lens epithelial cells into fiber cells with the upregulation of fiber marker proteins. More importantly, this process is independent of intracellular communication mediated by gap junctions. Together, these experimental findings may contribute to a broader understanding of the molecular mechanisms underlying cell differentiation and lens development.
Sequence of Vascular Events Following Photodynamic Therapy
Photodynamic therapy (PDT) induces a characteristic sequence of vascular changes. As reported in Michels and Schmidt-Erfurth (p. 2147), choroidal neovascularization (CNV) in human eyes is occluded by PDT with verteporfin in a dynamic rather than an immediate fashion. There is a relative selectivity which is demonstrated by non-perfusion of the CNV within one day after treatment. However, non-persistent thrombosis of the choriocapillary layer is slowly progressive and reaches its maximum as late as one week after PDT. The time-dependent progression of phototoxic events highlights the selectivity for CNV targeting, but choriocapillary closure may induce an angiogenic stimulus leading to reopening and progression of CNV.
Expression and Localization of Tenomodulin in Mouse Eyes
Tenomodulin (TeM) is a transmembrane-glycoprotein which contains a domain homologous to chondromodulin-I (ChM-I), a cartilage-derived angiogenesis inhibitor. TeM transcripts have been found to be expressed in tendons and ligaments. Oshima et al. (p. 1814) demonstrated that TeM transcripts are significantly expressed in the sclerocornea, the lens, and the retina. Adenoviral gene transduction into the retinal vascular endothelial cells for the autocrine secretion of the functional domain of TeM or that of ChM-I resulted in effective suppression of DNA synthesis and capillary-like formation of the cells. TeM and ChM-I might be the candidates for use in gene therapy approaches aimed at the treatment of ocular angiogenesis.
Molecular Organization of the Extraocular Neuromuscular Junction
Extraocular muscle (EOM) exhibits fundamental differences in innervation and neuromuscular junction properties from other skeletal muscles, which may determine its novel phenotype and disease response. This study by Khanna et al. (p. 1918) demonstrates that despite the differences in the EOM singly and multiply innervated fiber types, both exhibit conservation in the presence of the main junctional signaling pathway molecules. However, the observed differences in the extrajunctional distribution of signaling components of the sarcolemmal organizing network in some fibers is a finding that may be of fundamental importance in understanding the novel physiology and the unique susceptibility and resistance to diseases of extraocular muscle.
(No Title)
Mammalian extraocular muscles (EOM) are physiologically and biochemically unique when compared to non-ocular skeletal muscles. This study by McLoon and Wirtschafter (p. 1927) sought to determine if the process of continuous myonuclear addition the authors demonstrated in normal uninjured myofibers in adult EOM from both rabbits and mice might be a universal phenomenon in mammalian EOM. The EOM from adult uninjured monkeys and humans were shown to contain activated satellite cells that expressed hepatocyte growth factor, and the myogenic regulatory factors MyoD, myogenin, and Pax7. Cells in the satellite cell position also expressed Ki-67, a cell cycle marker. This supports the hypothesis that continuous myonuclear addition most likely occurs in primate and human EOM. This suggests new mechanisms that might be responsible for EOM sparing or involvement in skeletal muscle diseases.
Conjunctival Epithelial Cells as Immunoregulators
The conjunctival epithelium is an important target of pro-inflammatory cytokines (TNFa, IL-1b, IFNg) known to be present in ocular surface inflammatory disease states such as allergic conjunctivitis and dry eye disease. These cytokines are often simultaneously present on the ocular surface, yet their combined effects have not been examined. The study by Stahl et al. (p. 2010) reveals important differences in the pro-inflammatory effects (surface receptor expression and chemokine release) of IFNg compared to IL-1b and TNFa on primary cultures of conjunctival epithelial cells. Furthermore, combinations of cytokines are shown to enhance epithelial cell activation in ways that imply both redundant and divergent pathways, depending on the response being evaluated.
TNF in Endotoxin Induced Uveitis
Anti-TNF-a treatment reduces the LPS-induced increases in leukocyte rolling, adhesion and vascular leakage in a rat model of inflammatory uveitis. Additionally, increased levels of apoptosis in the vascular endothelium, ganglion cell, and inner nuclear layer and caspase 8 and 3 activation were observed by Koizumi et al. (p. 2184). Upon administration of a TNF-a inhibitor, significant reduction in the leukocyte rolling, adhesion and activation and apoptosis in all the above layers was observed. The quantitative analysis of vascular leakage revealed a significant decrease after treatment with etanercept. These results suggest the involvement of TNF-a in inflammatory uveitis and its potential use as a therapeutic agent in the reduction of ocular inflammation.
GDNF in Rod Photoreceptor Development and Survival
GDNF affects the development and survival of a series of neural and non-neural tissues during embryonic development. Rothermel and Layer (p. 2221) show that GDNF also plays a role during retinal development. GDNF increases the proliferation, the onset of differentiation and the survival of rod photoreceptors. Since programmed cell death of rod photoreceptors is a typical feature of several different retinal degenerations, GDNF and possibly other members of the GDNF family of peptides could represent a new therapeutic agent for the treatment of these diseases.
Microglia in Retinal Degeneration: Friend or Foe
The exact pathways from genetic miscoding to photoreceptor death in inherited retinal degenerations remain obscure. Increased microglial numbers in the outer retina during photoreceptor degeneration and increasing awareness of their cytotoxic potential have implicated microglia in contributing to photoreceptor death. The findings by Hughes et al. (p. 2229), that microglial numbers peaked 5 days after the height of photoreceptor apoptosis in the rds mouse and failed to upregulate iNOS, suggest that microglia are responding to, rather than causing, photoreceptor apoptosis. Furthermore, sialoadhesin expression by microglia during retinal degeneration may indicate blood-retinal-barrier breakdown, which has immune implications for sub-retinal gene therapeutic strategies.
A2E and DNA Damage
A2E, the fluorophore that accumulates in retinal pigment epithelial cells with age and in some retinal disorders, confers a susceptibility to blue light induced apoptosis. Previous work has shown that illuminated A2E undergoes photoxidative changes to generate reactive epoxides. Sparrow et al. (p. 2245), now show that DNA is at least one of the cellular constitutents damaged by photoreactive A2E. This work is likely to be significant to the understanding of A2E-associated injury to RPE cells in age-related macular degeneration.
The Mouse Nyctalopin Gene (mNyx) and Its Expression in the Rodent Retina
The complete form of X-linked congenital stationary nightblindness (CSNB1) is caused by mutations in NYX, a gene that encodes a novel member of the leucine-rich repeat (LRR) protein family. This study by Pesch et al. (p. 2260) shows that the murine orthologue mNyx is highly conserved with its human counterpart at the primary sequence as well at the gene structure level. In the rodent retina mNyx is expressed during all stages of postnatal development. In the adult retina, expression of mNyx is mostly confined to the inner nuclear and the ganglion cell layer. These findings propose an important function of nyctalopin in the inner retina and emphasize that the CSNB1 phenotype may at least in part result from a defect of the inner retinal circuitry.
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