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| March 2003 | Inside IOVS | Volume 44/3 |
Cyclooxygenase-2 (COX-2) Inhibition and Retinal Angiogenesis
Angiogenesis is a hallmark feature of retinal diseases such as proliferative diabetic retinopathy. Prostaglandins are involved in angiogenesis as inhibition of COX-2, a key enzyme in the prostaglandin pathway, attenuates angiogenesis in some cancers, arthritis and models of blood vessel growth. The novelty of the study by Wilkinson-Berka et al. (p. 974) is the localization of COX-2 to sites associated with retinal blood vessels, and the finding that selective COX-2 inhibition elicits an anti-angiogenic response in a rodent model of retinopathy of prematurity. These findings indicate a potential strategy for the treatment of angiogenic retinal disorders.
The TGIF Gene and High Myopia
The TGFb-induced factor TGIF gene was located on chromosome 18p11.3, where Lam et al. (p. 1012) had found a maximum LOD score of 3.3 in six high myopic families and investigated TGIF for mutations in 71 individuals with high myopia ≤-6.00D. Six SNPs showed significant difference (p<0.05) between patient and control in univariate analysis. Four of them cause codon changes: G223R, G231S, P241T and A262G. Multivariate analysis showed 657(T→G) to have statistical significance in the logistic regression model (OR 0.133; 95% C.I. 0.037 – 0.488; p=0.002). TGIF is a likely candidate gene for high myopia. Further studies are needed to identify the mechanism.
Extended Wear and Epithelial Basal Cell Movement
Extended wear (EW) with low oxygen transmissible contact lenses is known to suppress basal cell proliferation and surface cell exfoliation in the rabbit corneal epithelium. Ladage et al. (p. 1056) show that the movement of epithelial cells out of the basal cell layer towards the surface is also delayed during EW. Taken together, these findings suggest that EW is suppressing the overall turnover rate of the corneal epithelium. This may reduce the protective effectiveness of the corneal epithelium against infectious microorganisms and may partially explain why the rate of corneal infection is higher for extended contact lens wearers.
Müller Cell-Derived Growth Factors and Development of PVR
One retinal cell type which proliferates during proliferative vitreoretinopathy (PVR) is the Müller glial cell. Activation of PDGF receptors has been implicated in the development of PVR, and Müller cells from PVR retinas display upregulated expression of functional ATP receptors. Stimulation of ATP receptors in cultured cells increases the proliferation rate which is dependent on a release of growth factors, e.g. of PDGF. Milenkovic et al. (p. 1211) suggest that Müller cells may be implicated in the development of PVR, via ATP-induced release of growth factors, and that inhibition of ATP receptors may be useful to prevent uncontrolled proliferation in the retina.
Sustained Corticosteroid Delivery for VEGF Inhibition
Although clinical studies indicated that corticosteroids inhibit vascular hyperpermeability in macular edema, the underlying mechanisms are unclear, and sustained corticosteroid delivery to the posterior segment is a challenge. Kompella et al. (p. 1192) demonstrate that retinal pigment epithelial expression of VEGF, a potent inducer of vascular permeability, is inhibited by a corticosteroid (budesonide), providing an explanation for the previous clinical observations. In addition, this study demonstrates that subconjunctival injection of biodegradable nano- or micro- particles of budesonide sustain retinal drug delivery. These budesonide particulate systems will provide a convenient new therapeutic strategy for VEGF-mediated disorders of the eye and may eliminate the side effects of corticosteroids.
Female Gender and Estrogen Loss
Estrogen status influences the severity of many diseases in women. Its relation with age-related macular degeneration (AMD) has been recently addressed in multiple epidemiological studies. This hormone’s role in the severity of subRPE deposit formation was investigated in an experimental model for dry AMD. Cousins et al. (p. 1221) reported that depletion of 17 beta-estradiol increases severity of deposit formation in terms of thickness, continuity, and content. Also, endothelial changes and Bruch’s membrane thickening was observed. Supplementation with high-dose estrogen did not protect from subRPE deposit formation, which was correlated with loss of MMP-2 activity. The authors concluded that female gender and estrogen deficiency increases severity of subRPE deposit formation and that non-physiologic replacement may not be beneficial.
A Comprehensive System Detecting Autosomal Dominant Retinitis Pigmentosa Gene Mutations
Molecular diagnosis for autosomal dominant retinitis pigmentosa (adRP) remains complicated and often non-definitive due to the high heterogeneity of disease-causing genes. Kondo et al. (p. 1275) describe a system for detecting adRP mutations which involves linkage-based exclusion followed by exon screening of genes that could not be ruled out by genotyping. The comprehensiveness of this work, including the adRP gene-associated markers, nearly all of which are very close to the appropriate genes, provides a useful protocol for investigators to follow if confronted with a family with individuals affected by adRP.
Cone and RPE Degeneration in gnn Mutant
Besides being a major animal model for studies of developmental biology and genetics, zebrafish mutants play an increasing role as an animal model for hereditary degenerative diseases. The novel zebrafish visual mutant gantenbein (gnn), characterized by Biehlmaier et al. (p. 1287), exhibits morphological analogies to both cone dystrophies most commonly seen in age-related macular degeneration and to RPE alterations found in retinitis pigmentosa. The gnn zebrafish mutant may thus serve as an important model for further studies of the mechanisms underlying cone dystrophy and RPE alteration as well as for the possible interplay between both aspects of retinal degeneration.
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