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| March 2005 | Inside IOVS | Volume 46/3 |
The Mechanism of Action of Cyclosporin A in Retinoblastoma
Cyclosporin A (CSA) is used as an adjuvant to chemotherapy for the treatment of retinoblastoma (RB), with the rationale that it sensitizes tumor cells to chemotherapy by inhibiting the membrane-bound toxin efflux pump, P-glycoprotein. Eckstein et al. (p. 782) provide evidence that the therapeutic effects of CSA in RB are mediated by direct cytotoxicity. The authors show that CSA induces antiproliferative and apoptotic effects in RB cells at clinically achievable levels. These effects are associated with inhibition of calcineurin/nuclear factor of activated T-cells signaling, the same mechanism that accounts for CSA’s immunosuppressive effects. This signaling pathway, previously undescribed in RB, represents a promising target for pharmacological intervention in this disease.
Survival of Donor Cells after Limbal Transplant
At the time of keratoplasty, Djalilian et al. (p. 803) obtained corneal buttons from patients who had previously undergone limbal allograft transplantation and subjected the buttons to microsatellite analysis to determine the presence or absence of donor-derived epithelial cells. Donor-derived epithelial cells were documented up to 3.5 years after transplantation and found to be the predominat cell type on the corneal surface. These results indicate that donor limbal stem cells can survive and function in the long run. This finding further supports the use of systemic immunosuppression to prevent rejection of the donor tissue.
Doxycycline Inhibits TGF-β1-Induced MMP-9 via Smad and MAPK
MMP-9 (gelatinase B) plays an important role in ocular surface inflammation. This study by Kim et al. (p. 840) reveals that doxycycline markedly inhibits the TGF-b1-induced expression, production and activity of MMP-9 and activation of Smad, c-Jun N-terminal kinase (JNK), extracellular-regulated kinase (ERK), and p38 mitogen-activated protein kinase (MAPK) signaling pathways in human corneal epithelial cells. Its inhibitory effects are of similar magnitude to SP600125, PD98059 and SB202190, specific inhibitors of the JNK1/2, ERK1/2 and p38 pathways, respectively. These findings demonstrate that doxycycline inhibits TGF-b1-induced MMP-9 production through Smad and MAPK pathways, which may explain its efficacy in treating MMP-9-mediated ocular surface diseases.
Two Human 15-Lipoxgenases in the Human Cornea
The conversion of arachidonic acid (AA) by lipoxygenases (LOX) to various HETEs has been well described in a number of animal models with implications for roles in inflammation, wound healing, and cellular proliferation. Products of two different lipoxygenases are produced by animal corneas, but the human cornea primarily produces 15-HETE, a common product of either 15-LOX-1 or -2. Chang et al. (p. 849) report the presence of both 15-LOXs in the human corneal epithelium with similar mRNA levels. At the protein level, however, only 15-LOX-2 was detected. The two LOXs have different subcellular compartmentalization. This suggests that the products of the two 15-LOXs will also be compartmentalized and exert different physiologic effects. The broader implication is that the biologic functions of LOXs are not solely determined by their products -- subcellular localization of LOXs may also be an important factor.
Glatiramer Acetate Doesn't Prevent Secondary Degeneration after Partial Optic Nerve Transection
Glatiramer acetate (GA, COP-1, Copaxone) has been reported to reduce secondary degeneration of retinal ganglion cells (RGC). Secondary degeneration is cell death due to proximity to primarily injured and dying cells, and is thought to occur in neural tissue surrounding infarcts and trauma, and may play a role in glaucoma. Blair et al. (p. 884) measured RGC density in the inferior rat optic nerve after transecting the superior one-third of the optic nerve and found no protective effect of GA. This work suggests that GA does not have a therapeutic role in neuroprotection, at least after severe injury such as transection.
cAMP Treatment of Photoreceptors as Preparation for Retinal Transplantation
Retinal transplantation is a potentially exciting treatment for retinal degenerative disease. However, transplantation efforts in both animals and humans have thus far been unsuccessful. The paucity of graft-host synaptic interactions seems to be a primary impediment. Khodair et al. (p. 967) have been able to manipulate photoreceptor synaptic plasticity in vitro in a direction that may favor graft-host synaptic interaction. In grafts, photoreceptor axons retract toward the cell body and thus away from contact with host neurons. Increasing cAMP prevents this retraction. Manipulation of synaptic plasticity may be essential to successful graft-host integration.
Loss of the Stress-Responsive Transcription Factor HIF-2a Leads to Retinopathy
The ability to respond to environmental stresses is essential for all organisms. Hypoxia inducible transcription factor (HIF) complexes are activated by hypoxia, oxidative stress, altered redox states, and hypoglycemia. HIF members regulate genes involved in angiogenesis, glucose metabolism, cell survival/proliferation, oxygen transport, and oxidative stress response. In this study, Ding et al. (p. 1010) report that mice lacking HIF-2a exhibit retinal vascular abnormalities, retinopathy, and visual impairment. The cellular and molecular basis appears multifactorial in nature. Thus, impaired HIF signaling may be relevant to metabolic retinopathies, age-related macular degeneration, and ischemic retinopathies. Future studies will address the role of HIF-2a in these pathological eye states.
Choroidal Circulation in AMD
Reduced choroidal circulation has been reported in age-related macular degeneration (AMD). Grunwald et al. (p. 1033) investigated the relationship between foveolar choroidal blood flow and fundus features associated with increased risk for choroidal neovascularization (CNV). The authors found a systematic decrease in choroidal circulatory parameters with increasing risk for CNV development. The lowest circulatory parameters were observed in the eyes with the highest risk for CNV development (linear trend, P < 0.05), suggesting a role for ischemia in the development of CNV. Further studies are needed to elucidate whether a decrease in flow may trigger the development of CNV and whether decreased choroidal blood flow may help identify AMD patients at risk for visual loss.
Extracellular Redox Control of Apoptosis in the Retinal Pigment Epithelium
Oxidative stress is thought to have a role in the pathogenesis of age-related macular degeneration (AMD) on the basis of several laboratory, and human clinical and epidemiological studies. The current study by Jiang et al. (p. 1054) showed that changes in the extracellular cysteine and cystine redox status within the physiological range affect the sensitivity of cultured human retinal pigment epithelium (RPE) cells to oxidant-induced apoptosis. When there was increased oxidation of the extracellular cysteine pool, oxidative injury to the RPE through mitochondria-dependent mechanisms was potentiated. Manipulation of the plasma thiol/disulfide redox status by antioxidant supplementation and other dietary interventions may therefore have clinical implications in the prevention and treatment of AMD.
Angiotensin and the Developing Retina
Emerging evidence suggests that angiotensin promotes angiogenesis in ischemic retinopathies such as retinopathy of prematurity. Little is known about whether this occurs in the developing retina. Using transgenic Ren-2 rats that overexpress renin and angiotensin in the retina, Sarlos and Wilkinson-Berka (p. 1069) identified all components of the renin-angiotensin system (RAS) in the inner retina. Up-regulation of the RAS in the Ren-2 rat was associated with enhanced developmental retinal angiogenesis, which did not occur in age-matched Sprague Dawley rats. These results, taken together with previous findings, suggest that a retinal RAS may influence retinal vascular growth in both normal development and disease.
Angiotensin II Type 1 Receptor Blockade Inhibits Retinal Neovascularization
The renin-angiotensin system is an important controller of systemic blood pressure. Recently, several studies have demonstrated that blockade of this system suppressed tumor neovascularization. Focusing on the inflammatory mechanisms that promote pathological, but not physiological, retinal neovascularization, Nagai et al. (p. 1078) investigated the differential effects of an angiotensin II type 1 receptor (AT1-R) antagonist on each type of retinal neovascularization in a murine model of ischemic retinopathy. They found that AT1-R signaling blockade leads to the selective suppression of pathological, but not physiological, retinal neovascularization via the inhibition of the inflammatory processes related to the pathological neovascularization.
Decreased Macular Arrestin and Rhodopsin with AMD
Ethen et al. (p. 769) evaluated the Minnesota Grading System (MGS) for eyebank eyes to discern changes in rod photoreceptor protein expression in donors at distinct stages of age-related macular degeneration (AMD). Expression of rhodopsin and arrestin was evaluated by immunoblotting in the macular and peripheral regions of the neurosensory retina. A significant linear decline in both arrestin and rhodopsin content correlated with progressive MGS levels only in the macular region. This study has detected region-specific biochemical changes that correspond to progression of AMD as documented by the MGS. This is an initial step toward determining biochemical abnormalities in AMD.
Sensitization of Corneal Epithelial Migration by Substance P
Yamada et al. (p. 833) show using the substance P-derived tetrapeptide FGLM-amide that substance P shifted the dose-response relations for the induction of corneal epithelial migration not only by an IGF-1–derived peptide (C-domain peptide) but also by fibronectin or interleukin-6 to lower concentrations. This action of substance P was prevented by inhibitors of Ca2+- and calmodulin-dependent protein kinase II (CaM-PK II). These results indicate that substance P functions as an important modulator of corneal epithelial migration and wound healing via CaM-PK II, providing important insight into a new strategy for the treatment of corneal wounds.
Potential Role of ClC-3 Cl- Channel in Regulating Aqueous Humor Formation
Cl- secretion across the ciliary epithelium drives aqueous humor formation. Cl- efflux through channels of non-pigmented ciliary epithelial (NPE) cells limits the rate of Cl- transport, and thereby aqueous humor secretion. Despite its importance, the molecular identities of the swelling-activated, NPE-cell Cl- channels remain elusive. Using native bovine NPE cells, Do et al. (p. 948) determined the effects of a recently developed anti-ClC-3 antibody in modulating Cl- efflux. Intracellular perfusion with the selective anti-ClC-3 antibody delayed and inhibited the stimulation of swelling-activated Cl- currents, potentially decreasing Cl- release. This information will be useful for targeting ClC-3 in devising selective, effective therapies for glaucoma.
Variations in Macular Retinal Thickness with Myopia Using Optical Coherence Tomography
Using optical coherence tomography (OCT), Lim et al. (p. 974) measured macular retinal thickness in young ophthalmologically normal Asian myopes aged between 19 and 24. Overall average macular retinal thickness did not vary with increasing myopia or axial length. However, the point of maximum retinal thickness either side of the fovea, which is assumed to correspond to the parafovea, decreased with increasing axial length, while the point of minimum retinal thickness, which is assumed to correspond to the foveola, increased with increasing axial length. These variations in macular thickness should be considered in the evaluation of retinal diseases and glaucoma using the OCT.
Quantifying Distorted Perception
Krøyer et al. (p. 1017) present a novel perimetry technique that enables quantitative mapping of the visual distortion associated with epiretinal membranes. The distortion is expressed as a one-dimensional deviation score. This method may be useful for stratification of candidates for surgical removal of epiretinal membranes, when attempting to identify markers of outcome, and for extending the rationale for the clinical management of retinal disease with metamorphopsia.
Raman Spectroscopy is a Valid Method for Measuring Macular Pigment
Macular pigment (MP), composed of two dietary xanthophylls, lutein and zeaxanthin, forms a yellow spot in the center of the primate macula and is believed to protect against ocular diseases linked to oxidative stress, most notably, age-related macular degeneration. Currently, several techniques exist for measuring MP in vivo, of which Raman spectroscopy (RS) is a recently developed objective technique. In the study of Neelam et al (p. 1023) the validity of RS was tested by comparing Raman measurements of MP with the corresponding heterochromatic flicker photometry (HFP) readings. The results of this study have demonstrated that measurement of MP using RS is highly reproducible and is not subject to test-retest variability. Furthermore, a good degree of correlation was found between RS and HFP readings of MP, thus authenticating RS against HFP, a validated psychophysical technique of measuring MP.
Critical Flicker Frequency and Cataract Surgery Visual Outcomes
Bueno del Romo et al. (p. 1107) evaluated the phenomenon of critical flicker frequency (CFF) to predict the visual performance that might be expected after a cataract operation. CFF appears to be unaffected by cataract but is sensitive to macular disease. The predictions appear to be particularly useful where dense cataract is present. This rapid and simple clinical test holds promise as a method for predicting the visual outcome after cataract removal. Further work is required to fully investigate the temporal modulation sensitivity in order to optimise the measurement conditions.
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