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PubMed1995

Involvement of anterior chamber angle structures in disseminated histoplasmosis: report of three cases.

This study describes the involvement of anterior chamber (AC) angle structures in patients with disseminated histoplasmosis. The postmortem eyes from three patients (aged 33, 41, and 42 years, respectively) with disseminated histoplasmosis, two of whom had acquired immunodeficiency syndrome, were examined by light microscopy using hematoxylin-eosin, periodic acid-Schiff (PAS), and Gomori's methenamide silver (GMS) stains. Electron microscopy studies of the choroid were performed in one eye. Significant numbers of budding yeast forms of Histoplasma capsulatum measuring 2-5 microns in diameter were observed within the trabecular meshwork, Schlemm's canal and in the deep intrascleral plexuses. All eyes showed massive involvement of the choroidal vasculature, including the choriocapillaris. The organisms were observed freely as well as in small clusters within the cytoplasm of circulating monocytes. The vessels of the limbal conjunctiva (two eyes) and ciliary body (three eyes) contained many Histoplasma organisms. In one eye, several budding yeast were noted in an iris vessel and in occasional histiocytes within the ciliary muscle. Blood smears containing Histoplasma organisms were observed in two cases. None of the patients had an ophthalmologic examination prior to death. Involvement of the intravascular structures of the eye as well as the AC angle was observed in three patients with disseminated histoplasmosis. The fungus most likely reached the AC angle structures by direct hematogenous dissemination or via the aqueous humor by migration from vessels in the ciliary body and iris. An abnormal retrograde blood flow into the AC angle structures may have also played an important role. We suggested that the intraocular pressure be monitored in cases of suspected disseminated histoplasmosis to detect functional alterations indicative of a blockage in the outflow channels.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Herpes simplex virus mediated gene transfer to primate ocular tissues.

We evaluated the feasibility of delivering a gene into monkey eyes using a replication-competent herpes simplex virus (HSV) type 1 ribonucleotide reductase mutant (hrR3) expressing the Escherichia coli lacZ gene. To determine the efficiency of in vitro HSV-mediated gene transfer, cultured human trabecular meshwork (HTM) and human ciliary muscle (HCM) cells were infected with hrR3 and beta-galactosidase activity was measured histochemically. Six cynomolgus monkey eyes received viral injections into the anterior chamber (2 x 10(7) pfu) and/or the vitreous (5 x 10(7) pfu), and the distribution of cells expressing lacZ was evaluated. In vitro, both cultured HTM and HCM cells displayed multiplicity-dependent beta-galactosidase activity. In vivo, intracameral and/or intravitreal injection resulted in transgene expression in TM cells and in non-pigmented ciliary epithelial cells (NPE), but not in CM cells. Transgene expression was also detected in retinal pigmented epithelial (RPE) cells and sporadic retinal ganglion cells (RGC) in eyes receiving virus intracamerally and intravitreally respectively. We observed significant inflammation in the anterior chamber, TM and CM in virus-injected eyes, along with mild vitritis and retinitis. This study demonstrates successful gene transfer using hrR3 as a vector in human ocular cells and in ocular tissues in living monkeys. Further investigation of the etiology of the inflammatory response, possible cytotoxicity, and limited duration of transgene expression is necessary in order to make this technique clinically applicable.

Animals↗
PubMed2000

Glaucoma in primates: cytochrome oxidase reactivity in parvo- and magnocellular pathways.

PURPOSE: To evaluate the differential effects of ganglion cell depletion from experimental glaucoma on the relative metabolic activities of neurons in the parvo (P)- and magno (M)-cellular visual pathways of the macaque visual system. METHODS: Monocular experimental glaucoma was induced in monkeys (Macaca mulatta and M. fascicularis) by applying a laser to the trabecular meshwork to increase intraocular pressure (IOP). After other behavioral and electrophysiological studies, the lateral geniculate nuclei (LGNs) and the primary visual cortices were analyzed for functional afference from surviving ganglion cells, indicated by cytochrome oxidase (CO) histochemistry. RESULTS: CO reactivity (COR) indicated a general reduction in neural metabolism with increasing severity of glaucoma. COR in the LGNs was reduced to the same degree in both the P- and M-cellular layers. In layer 4Cbeta of the V1 cortex, the reactivity was always reduced more than in the layer 4Calpha division. CONCLUSIONS: Experimental glaucoma in monkeys reduces visual afference to the central nervous system, thereby reducing the metabolic drive as indicated by COR. The detrimental effect of glaucoma did not appear to be any greater for the M-cell, rather than the P-cell pathway in the LGN or in the visual cortex. Both are affected by the duration and severity of the experimental glaucoma. Overall, the alterations in metabolism of neurons in the parallel visual pathways supplied by the Palpha and Pbeta ganglion cells do not suggest that tests based on the functional properties of one or the other would provide optimal assessment of glaucoma.

Animals↗
PubMed1992

Changes in reversal of cupping in experimental glaucoma. Longitudinal study.

BACKGROUND: The authors prospectively and longitudinally studied changes in optic disc topography during spontaneous reduction of intraocular pressure (IOP) in five monkeys with experimental glaucoma, using a computerized image analyzing system (Topcon IMAGEnet). METHODS: Glaucomatous optic neuropathy was produced in one eye of each animal by repeated argon laser photocoagulation of the trabecular meshwork. The duration of follow-up was 12 months. After laser treatment, IOP fluctuated and tended to increase. Spontaneous reduction in IOP was frequently observed during follow-up. Changes in optic disc parameters (vertical and horizontal cup-to-disc ratios, rim area/disc area, cup volume/disc area) that accompanied a given magnitude of spontaneous reduction in IOP at the early stage of glaucoma (first 4 months of follow-up) were compared with those at the later stage of glaucoma (last 4 months of follow-up). RESULTS: All optic disc parameters improved significantly during IOP reduction at each stage of glaucoma. Although there was no significant difference between the two stages in the magnitude of IOP reduction, the extent of improvement in each disc parameter was significantly less in the later stage than in the early stage. In both stages, reversal of cupping occurred symmetrically in the vertical and horizontal dimensions. Expansion of the cup occurred symmetrically in the early stage, but this was predominantly vertical in the later stage. CONCLUSION: These results suggest that the extent of cupping reversal after IOP reduction may decrease with progressive glaucomatous damage in primate glaucoma.

Animals↗
PubMed1986

Quantitative analysis of 'plaque material' in the inner- and outer wall of Schlemm's canal in normal- and glaucomatous eyes.

The amount of plaque material derived from the sheaths of the elastic-like fibers in the cribriform layer of the trabecular meshwork (sheath-derived or SD plaques) was quantitatively evaluated in normal eyes and in trabeculectomy specimens of chronic simple, intermittent angle closure, and pseudoexfoliation glaucoma. The amount of SD plaque material increases with age but no correlation between age and SD plaques was found in any of the glaucomas evaluated. In comparison to normal eyes, the amount of SD plaque material was significantly greater in cases of chronic simple glaucoma and in cases of intermittent narrow angle glaucoma, but not in pseudoexfoliation glaucoma. In the latter, number and distribution of SD plaques resembled those of normal eyes. SD plaques were also found in the outer wall of Schlemm's canal. In normal eyes there was a correlation between outer-wall plaques and age as well as between inner- and outer-wall plaques. These correlations were not found in the different types of glaucoma. Our findings indicate that in addition to the age-related increase in plaque material, there is in glaucomatous eyes some plaque material which is distributed unevenly in the inner- and outer-wall of Schlemm's canal. This additional material was not found in pseudoexfoliation glaucoma, indicating that elevated intraocular pressure alone can not be responsible for plaque formation.

Adolescent↗
PubMed2000

Expression of adenylate cyclase subtypes II and IV in the human outflow pathway.

PURPOSE: It has been demonstrated that low doses of pilocarpine and other muscarinics substantially increase outflow facility in the isolated human outflow system devoid of ciliary muscle. These cholinergic-induced facility responses were thought possibly to be due to elevation of cAMP as a result of the presence of adenylate cyclases II (AC-II) and IV (AC-IV). Therefore, whether these isoforms are present in outflow tissues was examined. METHODS: Human anterior segments were perfused with carbachol (10(-9)-10(-5) M), and outflow facility and cAMP levels in the perfusate were measured simultaneously. Isolated trabecular meshwork (TM) were incubated with carbachol (10(-7) M), and the subsequent changes in cAMP were measured by radioimmunoassay. AC-II and AC-IV were characterized in ocular tissue with reverse transcription-polymerase chain reaction and in situ hybridization. RESULTS: Outflow facility increased, in a dose-dependent manner, by 10%, 16%, and 27% in response to 10(-9), 10(-7), and 10(-5) M carbachol, respectively. Similarly, cAMP increased by 9%, 70%, and 210% in response to 10(-9), 10(-7), and 10(-5) M carbachol, respectively. In addition, cAMP levels significantly increased by 39% in isolated TM strips incubated with 10(-7) M carbachol. AC-II was detected in most normal tissue examined, but not in any cultured cell lines or any glaucomatous tissue. AC-IV was also widely expressed in most normal tissues, faintly detected in some glaucoma tissue, but not detected in most cultured cells. CONCLUSIONS: The presence of AC-II and AC-IV in outflow tissues supports the hypothesis that cholinergics may indeed exert an effect on outflow facility, mediated by cAMP, which is independent of muscle contraction.

Adenylyl Cyclases↗
PubMed2002

Vitreal glutamate concentration in monkeys with experimental glaucoma.

PURPOSE: To investigate the hypothesis that the pathophysiology for the death of retinal ganglion cells in glaucoma involves excitotoxic effects from elevated concentrations of vitreal glutamate. METHODS: Experimental glaucoma was induced in the right eyes of 18 rhesus monkeys by argon laser treatments to the trabecular meshwork. After significant visual field defects and/or typical clinical glaucomatous changes had developed (1.5-13 months), the eyes were removed, and a sample (0.1-0.2 mL) of posterior vitreous was collected. Similar vitreous samples also were collected from eight untreated monkeys. The vitreous samples were analyzed in a masked fashion by high-pressure liquid chromatography in two independent laboratories. Mean levels of vitreal glutamate were determined for the treated and control eyes and differences between groups of eyes were evaluated by Student's t-test. RESULTS: The mean level (+/- SD) of vitreal glutamate in the eight untreated monkeys was 5.0 +/- 2.0 microM. A similar level of 5.7 +/- 1.8 microM was measured in the untreated eyes of monkeys with experimental glaucoma. In the glaucomatous eyes, the mean concentration of vitreal glutamate was 5.7 +/- 2.6 microM, which was not significantly different from the concentrations in the control eyes. CONCLUSIONS: Vitreal glutamate concentrations were not elevated in eyes with anatomic and functional damage from experimental glaucoma. This finding is in contradiction to previous reports that vitreal glutamate increases to toxic levels and probably contributes to glaucomatous damage of retinal ganglion cells.

Amino Acids↗
PubMed1999

Glucocorticoids regulate transendothelial fluid flow resistance and formation of intercellular junctions.

The regulation of transendothelial fluid flow by glucocorticoids was studied in vitro with use of human endothelial cells cultured from Schlemm's canal (SCE) and the trabecular meshwork (TM) in conjunction with computer-linked flowmeters. After 2-7 wk of 500 nM dexamethasone (Dex) treatment, the following physiological, morphometric, and biochemical alterations were observed: a 3- to 5-fold increase in fluid flow resistance, a 2-fold increase in the representation of tight junctions, a 10- to 30-fold reduction in the mean area occupied by interendothelial "gaps" or preferential flow channels, and a 3- to 5-fold increase in the expression of the junction-associated protein ZO-1. The more resistive SCE cells expressed two isoforms of ZO-1; TM cells expressed only one. To investigate the role of ZO-1 in the aforementioned Dex effects, its expression was inhibited using antisense phosphorothioate oligonucleotides, and the response was compared with that observed with the use of sense and nonsense phosphorothioate oligonucleotides. Inhibition of ZO-1 expression abolished the Dex-induced increase in resistance and the accompanying alterations in cell junctions and gaps. These results support the hypothesis that intercellular junctions are necessary for the development and maintenance of transendothelial flow resistance in cultured SCE and TM cells and are likely involved in the mechanism of increased resistance associated with glucocorticoid exposure.

Body Fluids↗
PubMed1997

[Effects of beta-adrenergic agonists and phosphodiesterase inhibitors on the outflow facility of the eye].

Changes in the outflow facility of perfused bovine eyes and in the shape of cells in cultured trabecular meshwork (TM) were studied after exposure to adrenergic drugs. Dobutamine, a selective beta 1 agonist caused confluent TM cells to change from their usual polygonal shape to a characteristic stellate shape. Salbutamol, a selective beta 2 agonist showed no effect. The phosphodiesterase (PDE) inhibitors, isobutylmethylxanthine (IBMX), theophylline, and caffeine were also very effective in producing this shape change. Epinephrine, isoproterenol, dobutamine or salbutamol did not increase the outflow facility, at temperatures of 22 degrees C or 36 degrees C, whereas theophylline, caffeine and IBMX increased the facility in a dose-dependent manner. The high concentrations of beta-adrenergic agents required to produce even a small change in outflow facility and the cell shape argue against the involvement of adrenergic receptor mediation; on the other hand, the enhancement of the effects of epinephrine by PDE inhibitors and a similar effect produced by cAMP suggest that the changes in the cell shape are produced by beta-receptor activation. The beta-adrenergic agents were ineffective on changing outflow facility but the PDE inhibitors were remarkably effective in producing both shape change and increasing facility. PDE inhibition has much greater influence on and around the outflow channels than pure beta-adrenergic agonists, at least in enucleated bovine eyes.

1-Methyl-3-isobutylxanthine↗
PubMed2006

Heat shock protein 90 is an essential molecular chaperone for nuclear transport of glucocorticoid receptor beta.

PURPOSE: Glucocorticoid sensitivity in glaucoma has been attributed to differences in the expression of the two glucocorticoid receptors, GRalpha and GRbeta. GRalpha undergoes steroid-dependent nuclear translocation by associating with a heat shock protein (Hsp)90 multiprotein heterocomplex. The nuclear transport of the non-ligand-binding GRbeta is still unknown. In this study, the roles of Hsp90 in the nuclear transport of GRbeta were investigated. METHODS: Immunocytochemistry and Western blot analysis were performed to detect the subcellular expression of GRbeta and Hsp90 in normal and glaucomatous trabecular meshwork (TM) cells, as well as in TM cells overexpressing GRbeta. The role of Hsp90 in GRbeta transport and stability were determined with the Hsp90 inhibitor, 17-AAG and the proteasome inhibitor lactacystin. Coimmunoprecipitation was performed to study GRbeta-Hsp90 complexes. RESULTS: In normal and glaucomatous TM cells, the nuclear concentration of Hsp90 correlates with the nuclear expression of GRbeta. Transfection with a GRbeta expression construct produces an overexpression and accumulation of GRbeta in the nucleus with a corresponding increase in nuclear Hsp90 amount. 17-AAG, a specific Hsp90 inhibitor, completely blocks the nuclear accumulation of GRbeta and consequently leads to the degradation of GRbeta in proteasomes. Coimmunoprecipitation experiments verify that GRbeta complexes with Hsp90 and the microtubule motor protein dynein. CONCLUSIONS: These data provide strong evidence that Hsp90 is an essential molecular chaperone for the nuclear transport of GRbeta. This transport appears to occur along micotubular tracks. Because nuclear GRbeta is important in regulating the glucocorticoid responsiveness, changes in GRbeta nuclear transport could influence subsequent responses that are often seen clinically, such as glucocorticoid resistance in some inflammatory and autoimmune diseases or enhanced glucocorticoid sensitivity in glaucoma.

Acetylcysteine↗
PubMed2002

Protein interactions with myocilin.

PURPOSE: To identify factors that interact in vivo with myocilin, a glaucoma gene product. METHODS: The yeast two-hybrid system with myocilin as the bait and a human skeletal muscle cDNA library as the prey was used to identify potential factors that interact with myocilin. Interactions were also examined in bovine trabecular meshwork (TM) cells through a mammalian two-hybrid system. Biochemical coimmunoprecipitation from both human TM cell lysate and in vitro translated proteins was also used to confirm results obtained from yeast analysis. RESULTS: Twenty positive clones isolated through yeast two-hybrid screening were deemed potential myocilin partners. Sequence analysis determined that two of them encoded for myocilin from amino acids 64 to 268. Myocilin was also found to interact with a component of the myosin motor protein, myosin regulatory light chain (RLC). The myocilin-myocilin and myocilin-RLC interactions revealed by the yeast system were further confirmed and demonstrated in cultured TM cells, by means of a mammalian two-hybrid system, and through biochemical coimmunoprecipitation, subcellular fractionation, immunofluorescence, and immunogold double labeling. CONCLUSIONS: These results indicate that myocilin can form homomultimers in vivo, independent of the olfactomedin-like domain. Further analysis established that the leucine zipper motif of myocilin may be necessary for the myocilin-RLC interaction. The interaction of myocilin with RLC, a component of the myosin motor protein complex, implies a role for myocilin in the actomyosin system, linking in turn this novel protein to functional status of the TM.

Animals↗
PubMed1993

Hyaluronan synthase immunoreactivity in the anterior segment of the primate eye.

The anterior segment of human and cynomolgus monkey eyes was investigated for the presence of hyaluronan (HA) synthesizing cells using a polyclonal antibody against the enzyme HA synthase (HAS). In the chamber angle region the most intense staining was seen in the cell membranes of the corneal endothelium and in monkey eyes in the cells covering the posterior extension of the cornea (the operculum). The trabecular meshwork cells of the uveal and inner corneoscleral lamellae were also intensely stained. On the other hand, no staining was observed in the trabecular cells of the outer corneoscleral and the cribriform meshwork. The cell membranes of the inner wall endothelium of Schlemm's canal were labelled only at their luminal surface. In the iris stroma and the trabeculum ciliare (the ciliary body band), labelled cells were also found, whereas the connective tissue of the ciliary muscle and the muscle itself did not contain HAS-positive cells. In the ciliary processes immunoreactivity was seen in the non-pigmented epithelial cells (NPE) covering the anterior tips of the processes, suggesting that HA found in the aqueous humor is produced by these cells. The pars plana NPE showed the most intense staining in the cells directly adjacent to the ora serrata region. The hyalocytes found in the neighborhood of the pars plana also showed intense HAS immunoreactivity. It is likely that both hyalocytes and NPE cells of the posterior pars plana release HA into the vitreous.

Aged↗
PubMed2001

Effects of protein kinase inhibitor, HA1077, on intraocular pressure and outflow facility in rabbit eyes.

OBJECTIVE: To elucidate the roles of protein kinase in regulating the intraocular pressure (IOP) and outflow facility in rabbit eyes. MATERIALS AND METHODS: A protein kinase inhibitor, 1-(5-isoquinolinesulfonyl)-homopiperazine (HA1077), was used. The IOP and the outflow facility were measured before and after topical, intracameral, or intravitreal administration of HA1077 in rabbits. Western blot analysis was performed to detect the 20-kd light chain of myosin in human trabecular meshwork (TM) cells and bovine ciliary muscle (CM) tissues. The cell morphologic condition and distribution of actin filaments and vinculin in TM cells were studied using cell biology techniques. Carbachol-induced contraction of isolated bovine CM strips following administration of HA1077 was examined in a perfusion chamber. RESULTS: In rabbit eyes, the administration of HA1077 resulted in a significant decrease in IOP in a dose-dependent manner. An increased outflow facility was also observed. Western blot analysis revealed the presence of 20-kd light chain of myosin in human TM cells and bovine CM tissues. In cultured human TM cells, exposure to HA1077 disrupted actin bundles and impaired focal adhesion formation. In addition HA1077 showed relaxation of bovine CM strips. CONCLUSIONS: Use of HA1077 caused a reduction in IOP and an increase in the outflow facility. The results of in vitro experiments suggest that the IOP-lowering effects of HA1077 may be related to the altered cellular behavior of TM cells and relaxation of CM contraction. The results of these studies suggested that protein kinase inhibitors have the potential to be developed into a treatment modality for glaucoma.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1997

Nonsulfhydryl-reactive phenoxyacetic acids increase aqueous humor outflow facility.

PURPOSE: The phenoxyacetic acid, ethacrynic acid (ECA), has potential use in glaucoma therapy because it acts to increase aqueous outflow in vivo and in vitro. In human trabecular meshwork (HTM) cell culture, ECA acts to change cell shape and attachment, effects that have been correlated with microtubule (MT) alterations and chemical sulfhydryl (SH) reactivity. To further explore these actions, we evaluated two non-SH reactive phenoxyacetic acids, inadcrinone and ticrynafen, and the MT-disrupting drug vinblastine. METHODS: Excised bovine and porcine eyes were perfused and outflow facility measured. Calf pulmonary artery endothelial and HTM cells were grown in culture and cytoskeletal effects evaluated after drug treatment. RESULTS: Indacrinone, ticrynafen, and vinblastine all caused an increase in outflow facility. In contrast with ECA, the outflow effects of indacrinone and ticrynafen were not blocked by excess cysteine. Although indacrinone and ticrynafen produced changes in cell shape in vitro, the beta-tubulin staining pattern of treated cells was not altered. Vinblastine caused cell shape change and the expected MT disruption. CONCLUSIONS: Phenoxyacetic acids can increase aqueous outflow facility and alter HTM cell shape and attachment in vitro by a non-SH, non-MT mechanism (which is probably shared also by ECA). These findings suggest the possibility of a broader class of glaucoma drugs that may be directed at the HTM. An understanding of the cellular target for these drugs has implications both for potential glaucoma therapy and for the cytoskeletal mechanisms involved in normal outflow function.

Animals↗
PubMed1992

Neuropeptide-induced [Ca2+]i transients in cultured bovine trabecular cells.

Various kinds of neuropeptides have been identified to be immunoreactive in the drainage angle of mammalian eyes. However, little is known about second messenger system involvement with these peptides. To determine whether some of these peptides are linked to a calcium signalling system in the trabecular meshwork (TM) cells, their effects on [Ca2+]i transients in fura-2 loaded cultured bovine TM cells were studied with a digital video-imaging system. The main findings of this study were: (1) The basal [Ca2+]i was 164.0 +/- 1.0 nM (mean +/- standard error of the mean, n = 668). (2) Of the neuropeptides examined, neuropeptide Y (NPY) (10(-6)M) is the most potent because it increased [Ca2+]i by about four-fold from the basal level. Other peptides--substance P, bombesin, calcitonin gene-related peptide, and vasoactive intestinal peptide induced smaller increases in [Ca2+]i. (3) We defined a response as positive if [Ca2+]i increased to a value that was 1.2-fold over the basal level. The majority of the TM cells reacted to NPY, whereas only 20-30% of the cells reacted to any of the other peptides. (4) The chelation of extracellular Ca2+ shortened the half-life of a NPY-induced response without affecting its latency. (5) NPY (10(-6)M) significantly increased the formation of inositol triphosphate following a 15 sec exposure. The same was the case for inositol monophosphate and inositol diphosphate. The results of this study suggest that in bovine TM cells, NPY stimulation is coupled to Ca2+ signalling through an increase in polyphosphoinositide turnover.

Animals↗
PubMed2005

Viscoelastic material properties of the peripapillary sclera in normal and early-glaucoma monkey eyes.

PURPOSE: To test the hypothesis that changes in the viscoelastic material properties of peripapillary sclera are present within monkey eyes at the onset of early experimental glaucoma detected by confocal scanning laser tomography (CSLT). METHODS: Short-term (3-9 weeks), moderate (< or =44 mm Hg) intraocular pressure (IOP) elevation was induced in one eye of each of eight male monkeys by lasering the trabecular meshwork. This procedure generated early experimental glaucoma, defined as the onset of CSLT-detected optic nerve head (ONH) surface change, in the treated eye. Scleral tensile specimens from the superior and inferior quadrants of the eight early-glaucoma eyes were subjected to uniaxial stress relaxation and tensile tests to failure and the results compared with similar data obtained in a previous study of 12 normal (nonglaucomatous) eyes. Linear viscoelastic theory was used to characterize viscoelastic material property parameters for each specimen. Differences in each parameter due to quadrant and treatment were assessed by analysis of variance (ANOVA). RESULTS: Peripapillary sclera from the early-glaucoma eyes exhibited an equilibrium modulus (7.46 +/- 1.58 MPa) that was significantly greater than that measured in normal eyes (4.94 +/- 1.22 MPa; mean +/- 95% confidence interval, P < 0.01, ANOVA). Quadrant differences were not significant for the viscoelastic parameters within each treatment group. CONCLUSIONS: The long-term viscoelastic material properties of monkey peripapillary sclera are altered by exposure to moderate, short-term, chronic IOP elevations and these alterations are present at the onset of CSLT-detected glaucomatous damage to the ONH. Damage to and/or remodeling of the extracellular matrix of these tissues may underlie these changes in scleral material properties.

Animals↗
PubMed2003

Gene microarray analysis of experimental glaucomatous retina from cynomologous monkey.

PURPOSE: To systematically explore changes in gene expression in the retina of monkeys with laser-induced glaucoma and to validate the microarray data on eyes with experimental glaucoma. METHODS: Glaucoma was induced in the right eye of four monkeys by repeated argon laser photocoagulation of the trabecular meshwork. The left eye served as the control. Retinas were isolated from glaucomatous and control eyes 30 days after photocoagulation. Gene expression changes were analyzed by human microarray chips which displayed a total of 9182 elements including Expression Sequence Tag (EST) clones. Changes in the expression of some genes were further confirmed by real-time PCR analysis. Immunohistochemical studies to examine protein expression of some gene products were also done for several genes that showed up- or downregulation by the microarray analysis. RESULTS: Two eyes with mild glaucoma and two with severe glaucoma were produced. In the mild and severe glaucomatous retina, the number of upregulated genes was 45 and 18, and the number of downregulated genes was 17 and 21, respectively. The number of genes that were up- or downregulated was 0.7% of all the genes examined. The real-time PCR analysis confirmed expression changes of some genes found in the microarray analysis. Ceruloplasmin was one of the upregulated genes, and it was found by immunohistochemical analyses to be expressed in Müller cells. CONCLUSIONS: Gene expression profiles in laser-induced glaucomatous monkey retinas were determined, and only a very small population of genes was up- or downregulated in glaucomatous eyes. Upregulation of ceruloplasmin protein was found in the Müller cells.

Animals↗
PubMed2005

Lentiviral mediated gene delivery to the anterior chamber of rodent eyes.

PURPOSE: To study the in vivo efficiency of lentiviral vectors in delivering genes to the trabecular meshwork (TM) of rodent eyes. METHODS: Lentiviral vectors were constructed using the elongation factor 1 alpha (EF-1alpha) promoter driving expression of the green fluorescent protein (GFP) gene. The viral construct was injected intracamerally through the peripheral cornea into the anterior chamber of live rodent eyes. Several variables were evaluated to determine the optimal conditions for TM cell transduction. These parameters included viral concentration, injection volume, needle rotation, and the modulation of anterior chamber current convections. Changes in intraocular pressures (IOPs) were monitored using a Tonopen XL. Signs of inflammation and corneal neovascularization were evaluated by slit lamp observation. Three weeks after injection, the eyes were enucleated and analyzed for GFP expression and distribution. RESULTS: A single intracameral viral dose between 10(7) and 10(8) pfu produced a high and evenly distributed expression of GFP in the TM and corneal endothelial cells. The cornea remained clear and no signs of inflammation were present during the course of the experiment. Moreover, no significant changes in IOPs were observed. CONCLUSIONS: A high transduction efficiency of TM and corneal endothelial cells can be effectively obtained after a single dose of recombinant lentivirus. The EF-1alpha promoter induces high expression of the reporter gene and is a reliable alternative to the CMV promoter when stable, long term expression is desired.

Animals↗