Effects Of Elevated Intraocular Pressure Research Articles

Role of T cell-induced autoimmune response in the pathogenesis of glaucoma.

This review aims to elucidate the role of T cell-induced autoimmune responses in the pathogenesis of glaucoma, focusing on the immunological changes contributing to retinal ganglion cell (RGC) damage. A comprehensive review of recent studies examining immunological mechanisms in glaucoma was conducted. This included analyses of T cell interactions, heat shock proteins (HSPs), and resultant autoimmune responses. Key findings from experimental models and clinical observations were synthesized to present a coherent understanding of immune dynamics in glaucoma. Glaucoma is a neurodegenerative disease marked by optic nerve atrophy and irreversible vision loss due to RGC damage. The disease is etiologically heterogeneous, with multiple risk factors and pathogenic mechanisms. Recent research highlights the dual immunomodulatory role of T cells in immune protection and injury. T cells, pre-sensitized by bacterial HSPs, can cross-react with endogenous HSPs in RGCs under stress, leading to autoimmune damage. Elevated levels of HSP autoantibodies and abnormal T cell activity have been observed in glaucoma patients, indicating a significant autoimmune component in disease progression. T cell-induced autoimmune responses are crucial in the pathogenesis of glaucoma, contributing to RGC degeneration beyond the effects of elevated intraocular pressure. Understanding these immunological mechanisms is vital for developing targeted neuroprotective therapies for glaucoma.

Effects of Elevated Intraocular Pressure on Retinal Ganglion Cell Density and Expression and Interaction of Retinal Aquaporin 9 and Monocarboxylate Transporters

Introduction: Astrocyte-to-neuron lactate shuttle (ANLS) plays an important role in the energy metabolism of neurons, including retinal ganglion cells (RGCs). Aquaporin 9 (AQP9), which is an aquaglyceroporin that can transport lactate, may be involved in ANLS together with monocarboxylate transporters (MCTs) to maintain RGC function and survival. This study aimed to investigate the impact of elevated intraocular pressure (IOP) on AQP9-MCT interaction and RGC survival. Methods: IOP was elevated in Aqp9 knock-out (KO) mice and wild-type (WT) littermates by anterior chamber microbead injection. RGC density was measured by TUBB3 immunostaining on retinal flat mounts. Immunolabeling, immunoblot, and immunoprecipitation were conducted to identify and quantitate expressions of AQP9, MCT1, MCT2, and MCT4 in whole retinas and ganglion cell layer (GCL). Results: Aqp9 KO and WT mice had similar RGC density at baseline. Microbead injection increased cumulative IOP by approximately 32% up to 4 weeks, resulting in RGC density loss of 42% and 34% in WT and Aqp9 KO mice, respectively, with no statistical difference. In the retina of WT mice, elevated IOP decreased the amount of AQP9, MCT1, and MCT2 protein and changed the AQP9 immunoreactivity and reduced MCT1 and MCT2 immunoreactivities in GCL. Meanwhile, it decreased MCT1 and increased MCT2 that interact with AQP9, without affecting MCT4 expression. Aqp9 gene deletion increased baseline MCT2 expression in the GCL and counteracted IOP elevation regarding MCT1 and MCT2 expressions. Conclusion: The compensatory upregulation of MCT1 and MCT2 with Aqp9 gene deletion and ocular hypertension may reflect the need to maintain lactate transport in the retina for RGC survival.

Effects of water drinking test on ocular blood flow waveform parameters: A laser speckle flowgraphy study.

The water-drinking test (WDT) is a provocative test used in glaucoma research to assess the effects of elevated intraocular pressure (IOP). Defective autoregulation due to changes in perfusion pressure may play a role in the pathophysiology of several ocular diseases. This study aims to examine the effects of WDT on ocular blood flow (in the form of pulse waveform parameters obtained using laser speckle flowgraphy) to gain insight into the physiology of ocular blood flow and its autoregulation in healthy individuals. Changes in pulse waveform parameters of mean blur rate (MBR) in the entire optic nerve head (ONH), the vasculature of the ONH, the tissue area of the ONH, and the avascular tissue area located outside of the ONH were monitored over time. Significant increases in the falling rate of MBR over the entire ONH and its tissue area and decreases in blowout time (BOT) of the tissue area were observed only at 10 minutes after water intake. Significant increases in the skew of the waveform and the falling rate were observed in the vasculature of the ONH at 40 and 50 minutes after water intake, respectively. In the avascular region of the choroid, the average MBR increased significantly up to 30 minutes after water intake. Furthermore, the rising rate in this region increased significantly at 20 and 40 minutes, and the falling rate and acceleration-time index were both significantly increased at 40 minutes after water intake. Our results indicate the presence of effective autoregulation of blood flow at the ONH after WDT. However, in the choroidal region, outside of the ONH, effective autoregulation was not observed until 30 minutes after water intake in healthy study participants. These pulse waveform parameters could potentially be used in the diagnosis and/or monitoring of patients with glaucoma.

Time-Dependent Effects of Elevated Intraocular Pressure on Optic Nerve Head Axonal Transport and Cytoskeleton Proteins

To study the time-dependent effects of elevated intraocular pressure (IOP) on axonal transport and cytoskeleton proteins in the porcine optic nerve head. Fifteen pigs were used for this study. Rhodamine-beta-isothiocyanate was injected into the vitreous of each eye to study axonal transport. IOP in the left eye was elevated to 40 to 45 mm Hg, and IOP in the right eye was maintained between 10 and 15 mm Hg. Cerebrospinal fluid pressure was also continually monitored. IOP was elevated for 3 hours (n = 7) or 12 hours (n = 8) before animal euthanatization. Antibodies to phosphorylated neurofilament heavy (NFHp), phosphorylation-independent neurofilament heavy (NFH), neurofilament light, neurofilament medium (NFM), microtubule, and microtubule-associated protein (MAP) were used to study the axonal cytoskeleton. Confocal microscopy was used to compare axonal transport and cytoskeleton change between control and high IOP eyes in different laminar regions and quadrants of the optic nerve head. Results from these experiments were also compared with 6-hour elevated IOP data from an earlier study. Three hours of IOP elevation caused a decrease in NFH, NFHp, and NFM within laminar regions, with no demonstrable change in axonal transport. Changes to MAP and microtubules were only seen after 12 hours of IOP elevation. Axonal transport change occurred in a time-dependent manner with peripheral nerve bundle changes occurring earlier and being greater than central nerve bundle changes. Time-dependent changes in axonal transport and cytoskeletal structure in the optic nerve head provide further pathogenic evidence of axonal damage caused by elevated IOP.

Effects of elevated intraocular pressure on mouse retinal ganglion cells

We developed and characterized a mouse model of elevated intraocular pressure (IOP) to investigate the underlying cellular and genetic mechanisms of retinal ganglion cell (RGC) death. IOP was unilaterally increased in C57BL/6J mice by photocoagulation of the episcleral and limbal veins. IOP was measured using an indentation tonometer. RGC survival was measured by retrograde labeling using DiI applied to the superior colliculous. The mechanism of RGC death was investigated using TUNEL staining, immunostaining for cleaved caspase-3, and Western blot for Bcl-2 and Bax expression. RT-PCR was used to measure changes in Bcl-2, Bax, Bad, Bak, P53, ICE and Fas. Mean IOP was increased in the treated eyes from 13 ± 1.8 to 20.0 ± 2.8 mm Hg at four weeks and 17 ± 2.2 mm Hg at eight weeks. RGC loss was 15.6 ± 3.4% at two weeks and 27.3 ± 4.5% at four weeks after laser photocoagulation. TUNEL staining and caspase-3 positive cells were increased in the ganglion cell layer (GCL) in the treated eyes and seldom found in the control eyes. Bcl-2 expression in control group was higher than in the experimental group, while Bax expression in the control group was less than in experimental group. This mouse model resulted in a consistent, sustained increase in IOP with a reduction in the number of RGCs in the treated eye. The RGCs in eyes with elevated IOP were TUNEL-positive, with increased caspase-3 and decreased Bcl-2, consistent with apoptosis as the mechanism of neuronal cell death.

Effect of elevated intraocular pressure on endothelin-1 in a rat model of glaucoma

The role of endothelin-1 (ET-1) a potent vasoactive peptide, in glaucoma pathogenesis is receiving increasing attention, particularly in astroglial activation in optic nerve damage. Our laboratory has also shown that ET-1 treatment causes proliferation of cultured human optic nerve head astrocytes to possibly initiate astrogliosis. ET-1 is distributed in retina, optic nerve, and ciliary epithelium, however the effects of elevated intraocular pressure (IOP) (as seen in glaucoma) on ET-1 and ET B receptors are not clearly understood. In the present study, the levels of immunoreactive ET-1 (ir-ET-1) in aqueous humour (AH) and optic nerve head (ONH) were determined in the Morrison elevated IOP model of glaucoma. Additionally in the ONH of these rats, immunohistochemical analyses of ET B receptors and glial fibrillary acidic protein (GFAP; a marker for astroglial cells and for astrogliosis) were performed. There was 2- to 2.5-fold increase in AH ir-ET-1 levels for rats subjected to elevated IOP, compared to their respective controls. In the Morrison rat model of glaucoma, elevated IOP increased optic nerve ir-ET-1 with concomitant increases in ir-ET B and ir-GFAP labelling (possibly indicative of astrogliosis and hypertrophy). As seen in brain astrocytes subjected to neurotrauma, the present findings are suggestive of ET-1’s role in astroglial activation, particularly in response to elevated IOP in glaucoma.

Effects of increased intraocular pressure on rat retinal ganglion cells

The effects of elevated intraocular pressure (IOP) on the morphology of rat retinal ganglion cells (RGCs) was analyzed in this study. After cauterizing two limbal derived episcleral veins, IOP in experimental eyes was elevated 1.5–1.8 times that of control. RGCs of experimental and control eyes were analyzed after: bilateral tectal injections of Fluoro-Gold, and application of fluorescent dye crystals, 4-Di-10-ASP to the proximal stump of the cut optic nerve, at different time intervals after IOP elevation. The RGCs in control and experimental eyes were evaluated at 4, 6, 8, and 10 weeks by counting, as well as by determining the soma diameter. The dendritic field of three types (I, II, III) of RGCs between control and experimental eyes were also studied at 4,6,10 weeks after IOP elevation. At every time point, the number of cells in experimental eyes were significantly less than those of the control eyes. The average retinal ganglion cell death was 3–4% per week in the eyes with elevated IOP. The soma and dendritic field diameter of the RGCs in the experimental eyes were significantly larger in all cell types. However, types I and III cells expanded their dendritic fields more rapidly than type II cells. Furthermore, dendritic fields of surviving RGCs in experimental eyes occupied about the same extent of the retina as the controls. The increase in soma diameter and expansion of dendritic fields in the remaining RGCs in eyes with elevated IOP suggests the existence of plasticity in adult retina.

Effects of Elevated Intraocular Pressure on Haemoglobin Oxygenation in the Rabbit Optic Nerve Head: A Microendoscopical Study

Intraocular pressure dependent reactions of optic nerve head vasculature and intracapillary haemoglobin oxygenation (HbO2; oxygen saturation) were studied in the center and at the rim of the rabbit optic nerve head (ONH) as well as in the choroid, by a new combination of microendoscopy and simultaneous haemoglobin spectrophotometry.In 13 anesthetized albino rabbits the vasculature and the intracapillary Hb-oxygenation were studied by a microendoscope which was introduced into the eye bulb. Photometric measurements were performed via a beam splitter with the Erlangen micro-lightguide spectrophotometer (EMPHO) from the center of the endoscopic picture. The haemoglobin oxygenation was calculated by real time analysis of the spectral curves. Intraocular pressure was elevated stepwise from 20–80 mmHg.At the rim of the optic nerve head the vascular diameters as well as the intracapillary HbO2-values were stable till an intraocular pressure of 60 mmHg and decrease after IOP elevation to 70 and 80 mmHg. In contrast, in the center of the optic nerve head and in the choroid these parameters decline already from 40–50 mmHg on. At an IOP of 60 mmHg (P<0.01) and 70 mmHg (P<0.05) HbO2is significantly lower in the ONH center than at the rim. In the center and the choroid HbO2is well maintained between 20 and 40 mmHg. After pressure release at the end of the experiment HbO2increased to 94.3±4.6% (rim) and 98.8±1.5% (center) of the initial value at 20 mmHg (difference not significant).By the high spatial resolution of this new optical method we were able to demonstrate that the center of the optic nerve head is more sensitive to changes in intraocular pressure than the optic nerve head rim. Thus, tissue damage after critical haemodynamic and oxygenation parameters seems more probable in the relatively poor perfused center of the ONH than in the overperfused rim.

Experimental Glaucoma

To investigate the relationship between intraocular pressure (IOP) and the progression of visual field defects caused by experimental glaucoma in Macaca mulatta monkeys. Perimetric fields were measured by behavioral methods in 18 rhesus monkeys during the course of unilateral glaucoma produced by argon laser treatment of the trabecular meshwork. The monkeys' IOPs were measured by applanation tonometry. Visual field defects were quantified by the mean deviation perimetric index from Humphrey Field Analyzer C24-2, model 630 (Humphrey Allergan, San Leandro, CA, U.S.A.), full-threshold data. The monkeys' eyes demonstrated considerable variability in their susceptibility to pressure-induced neural damage. For 10 of the monkeys, significant field defects were correlated with the increases in their IOPs and the defects progressed monotonically to end-state glaucoma. For the other monkeys, the mean deviation index was not well correlated with IOP; some eyes withstood pressures in excess of 35 mm Hg for several months before significant reduction in visual sensitivity. However, once they began, the rate of progression of field defects was similar across subjects. Laser ablation of the trabecular meshwork in monkeys provides a model for investigations of the effects of IOP that are not confounded by other ocular or visual disorders. Behavioral perimetry showed the same intersubject variability in the effects of elevated IOP on visual field sensitivities of monkeys that are common with high-tension glaucoma or ocular hypertension in patients. Thus, these investigations provide additional support for the use of the model for a wide variety of clinical investigations on glaucoma.

A clinical study of peripapillary crescents of the optic disc in chronic experimental glaucoma in monkey eyes.

We produced chronic experimental glaucoma in 41 monkey eyes and assessed the long-term effects of elevated intraocular pressure on the presence of, and changes in, peripapillary crescents. Three readers independently plotted peripapillary crescent size and location using stereo fundus photographs before and after chronic elevation of intraocular pressure in 41 monkey eyes. Crescents were found in a majority of normal eyes. After chronically elevated intraocular pressure, new peripapillary crescents developed in only two eyes. Using planimetric analysis, crescent size was enlarged in five (22%) of the 23 eyes with preexisting crescents. Preexisting crescents became more apparent without change in size in a majority of eyes (reader A, 15 [68%] of 22 eyes; reader B, 17 [74%] of 23 eyes; and reader C, 13 [68%] of 19 eyes). We conclude that peripapillary crescents are often present in normal monkey eyes but that they do not often undergo dramatic changes in size with chronic intraocular pressure elevation. The presence of a crescent was not significantly associated with the development of optic disc cup enlargement in the experimental monkey eye.