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| January 2007 | Inside IOVS | Volume 48/1 |
Inhibition of Intercellular Communication in Corneal Endothelial Cells by Thrombin
D'hondt et al. (p. 120) demonstrate that thrombin inhibits the intercellular Ca2+ wave propagation in bovine corneal endothelial cells by activating PAR-1 receptors. This results in inhibition of paracrine intercellular communication mediated by ATP release via connexin hemichannels and in a small reduction of gap junctional intercellular communication. The effect involves phosphorylation of the myosin light chain by myosin light chain kinase-, PKC-, and Rho kinase-sensitive pathways and suggests an influence of the actin cytoskeleton on intercellular communication in the corneal endothelium. In situations of inflammatory stress, hypoxia, and aging, such a block could be a defense mechanism by limiting "bystander effects."
Thrombin Generation in the Avascular Cornea
It has long been thought that thrombin generation in tissues requires vascular injury and leakage of coagulation factors. Ayala et al. (p. 134) show that extracts of non-wounded avascular corneal stroma contain components of the intrinsic and extrinsic coagulation pathways that upon activation generate thrombin, which generates fibrin clots. The cornea also contains mRNA for components and inhibitors of these pathways. Generation of thrombin under conditions not requiring vascular release of coagulation proteins suggests an intracorneal mechanism for not only forming fibrin but also activation of the thrombin-sensitive, protease-activated receptors, which can stimulate synthesis of cytokines, chemokines, and proteases and induce fibrosis.
FOXC1 and PITX2 Gene Defects and Glaucoma Prognosis in Axenfeld-Rieger Malformation
Axenfeld–Rieger malformation (ARM) is a rare autosomal dominant disorder that affects the anterior segment of the eye. The most important clinical consequence of this disease is glaucoma. Approximately 40% of ARM patients have defects in the two known genes, FOXC1 and PITX2. Strungaru et al. (p. 228) describe the results of a retrospective study on the largest cohort of ARM patients studied to date, with known FOXC1 and PITX2 defects. The goals of this study were to gain a better understanding of the ARM-associated glaucoma and insight into the best glaucoma treatment for ARM patients with known genetic defects. This analysis revealed a strong correlation between the type of defect and the severity of prognosis of glaucoma, and provides useful diagnostic criteria to identify the gene responsible for ARM. It is also apparent that current medical therapies are usually not successful to treat glaucoma in ARM patients with FOXC1 or PITX2 alterations. This information will provide physicians additional insight in diagnosing and treating patients with ARM.
Granulocyte Macrophage Colony-Stimulating Factor and Herpetic Stromal Keratitis
Despite significant research efforts and advances in diagnosis and therapy, herpetic stromal keratitis (HSK) remains a major cause of corneal blindness in humans. In the study by Duan et al. (p. 277), the cellular source and role of the cytokine granulocyte macrophage colony-stimulating factor (GM-CSF) on neutrophils in relation to the immunopathogenesis of human HSK was explored. GM-CSF was detected in corneas of HSK patients but not in controls. In vitro studies showed that human corneal resident cells, both corneal fibroblasts and epithelial cells, stimulated with HSK-associated proinflammatory cytokines, secreted GM-CSF capable of inducing neutrophil survival, activation, and even secretion of the major neutrophil chemoattractant interleukin 8. Because chronic inflammation is critical to the loss of corneal function in the setting of HSK, the data suggest that GM-CSF may represent a promising therapeutic target to antagonize neutrophil-mediated corneal tissue destruction.
Diabetic-like Vascular Degeneration in Retinal Ischemia and Reperfusion Model
Degeneration of retinal capillaries and retinal nerves occurs in diabetic retinopathy, and the neurodegeneration apparently precedes the capillary degeneration. The relation between the degeneration in these two compartments, however, has not been experimentally studied. Zheng et al. (p. 361) report that acute ischemia followed by reperfusion in the eye, known to cause retinal neurodegeneration, also causes a diabetes-like degeneration of retinal capillaries. The capillary degeneration develops only after the neurodegeneration is advanced, and both can be inhibited by aminoguanidine. This ischemia and reperfusion model should be valuable to the study of the relationship between the neuroglial retina and its vasculature, and to the screening of potentially therapeutic treatments to inhibit diabetic retinopathy.
Interferon Therapy, Retinal Blood Flow, and Hepatitis C
Although interferon (IFN) therapy is known to be associated with ocular side effects, the exact mechanism of IFN-induced retinopathy is still unclear. Nagaoka et al. (p. 368) evaluated the effect of IFN therapy on retinal microcirculation in 36 patients with chronic hepatitis C who were treated with high-dose IFN. This study has shown that retinal blood flow increases in association with IFN therapy in these patients, and the increase in RBF was independently correlated with a decrease in the red blood cell count. In addition, the present data suggests that retinal vascular dysfunction might be associated with IFN-induced retinopathy.
Protection from PDT Toxicity by Neurotrophic Factors
Verteporfin photodynamic therapy (PDT) is used to treat choroidal neovascularization in patients with age-related macular degeneration but can also damage the overlying retina. Paskowitz et al. (p. 430) studied the protective effects of injecting neurotrophic factors prior to PDT in normal rats. Brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), a combination of BDNF and CNTF, or pigment epithelial cell-derived growth factor (PEDF) all increased photoreceptor survival. However, as measured using multifocal ERG, only BDNF improved retinal function, measured using multifocal ERG. Neuroprotection was sustained through two rounds of BDNF injection and PDT, suggesting its potential value for patients who require multiple treatments.
Egr-1 Deletion Produces Myopia in Mice
In both chickens and primates, it could be shown that ZENK/Egr-1 expression is correlated with induced myopia and hyperopia. Schippert et al. (p. 11) present an investigation of the visual basics of the Egr-1 knock-out mouse model. It could be shown that homozygous Egr-1 knock-out mice develop a relative myopic shift in refraction. These mice also have longer eyes (difference in axial length about 59 microns at the age of 42 days) with additional minor effects on anterior chamber depth and corneal radius of curvature. This study suggests that homozygous loss of Egr-1 has functional consequences for mouse vision.
Retinal Arteriolar and Venular Caliber, the Arteriole to Venule Ratio, and Systemic Vascular Disease
The arteriole to venule ratio (AVR) has long been used as a measure of arteriolar narrowing and has recently been shown to convey unique prognostic information on the risk of cardiovascular disease such as hypertension, coronary heart disease and stroke. However, the AVR has several important limitations that Liew et al. (p. 0000) highlight in their article. AVR loses information compared to analyses using the directly measured retinal arteriolar and venular calibers, and the authors recommend a modeling strategy that incorporates both measures to maximize predictive information and reduce confounding. This method will be useful to researchers and clinicians hoping to incorporate evaluation of retinal vessels in cardiovascular risk assessment.
Normal Corneal Shape Is Influenced by Eyelid Morphology
Speculation has existed for many years that pressure from the eyelids may be involved in the aetiology of corneal astigmatism; however, the exact cause of astigmatism remains unknown. Read et al. (p. 112) report on a number of significant associations found between parameters describing the shape of the cornea and parameters describing the morphology of the palpebral fissure in a population of young adult subjects. Correlations were found between parameters describing the axis of corneal astigmatism and the angle of the eyelids. The associations found in this study support a model of astigmatism development where the eyelids are involved; however, they do not prove causation.
The Phenotype of Limbal Epithelial Stem Cells
Figueira et al. (p. 144) studied 'stem cell pathway' related gene expression in the human fetal limbus and adult human limbal epithelium. Microarray experiments were used to simultaneously study the differential expression of 266 stem cell pathway related genes in limbal and central regions of these tissues. The identification of a phenotypic profile unique to the human fetal and adult limbal epithelium will help research groups to identify limbal stem cells for in vivo and in vitro studies directed at improving the sucess of allolimbal transplants or success of in vivo and ex vivo expansion of limbal epithelial cells.
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