Mediation of laser trabeculoplasty-induced matrix metalloproteinase expression by IL-1beta and TNFalpha.
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PURPOSE: Laser trabeculoplasty of the anterior uveal region of the trabecular meshwork induces sustained matrix metafloproteinase expression within the juxtacanalicular region of the meshwork. Studies were conducted to test the hypothesis that a factor mediates this response and to identify the factor. METHODS: Human anterior segment organ cultures were subjected to laser treatment using standard clinical parameters and were returned to culture for 8 hours. The resultant 8-hour-conditioned culture medium was then tested for factor activity by evaluating its ability to produce two typical trabecular responses to laser treatment, that is, to induce stromelysin expression or to trigger cell division, when applied to fresh organ cultures or to cell cultures. Confocal immunohistochemistry of the laser-treated organ cultures and western immunoblot analysis of the conditioned medium were used to evaluate changes in potential candidates for the factor activity. The ability of the interleukin (IL)-1 receptor antagonist (IL-1ra)- and of tumor necrosis factor alpha (TNFalpha)- blocking antibodies to eliminate the stromelysin induction was evaluated. RESULTS: Medium conditioned for 8 hours induced typical trabecular cell division in anterior segment organ cultures. Medium conditioned for 8 hours, but not for 30 minutes, induced typical increases in stromelysin expression in these organ cultures and in cell cultures. After 8 hours, both trabecular cells in laser-treated organ cultures and in the conditioned medium contained elevated levels of IL-1beta and TNFalpha. The laser-treated organ cultures contained elevated levels of IL-1alpha, but it was not secreted into the medium. The ability of conditioned media to induce stromelysin expression was partially blocked by either the IL-1ra- or the TNFalpha-blocking antibody. CONCLUSIONS: Laser trabeculoplasty induces the expression and secretion of both IL-1beta and TNFalpha within the first 8 hours after treatment. These cytokines then mediate increased trabecular stromelysin expression. Putatively, this initiates remodeling of the juxtacanalicular extracellular matrix, a likely site for the aqueous outflow resistance, and thus restores normal outflow facility. (+info)
Air bags and ocular injuries.
(18/421)
PURPOSE: This investigation retrospectively examined ocular injuries associated with air bag deployment to gain a better appreciation of potential risk factors in motor vehicle accidents. National statistics regarding the efficacy of air bags were reviewed. METHODS: Review of the literature from 1991 to 1998 identified 44 articles describing 97 patients with air-bag-induced ocular injuries. Variables extracted from each case were age, sex, height, position in the car, eye wear, vehicle impact speed, visual acuity, and specific ocular injuries. RESULTS: Corneal abrasions occurred in 49% of occupants, hyphemas in 43%, vitreous or retinal hemorrhages in 25%, and retinal tears or detachments in 15%. The globe was ruptured in 10 patients. Patients involved in higher-speed accidents (over 30 mph) sustained a greater percentage of vitreous or retinal hemorrhages and traumatic cataracts, while those at slower speeds were more prone to retinal tears or detachments. In a subset of 14 patients with serious ocular injuries, the impact speed of 11 patients was recorded at 30 mph or less. Slower speed may be a risk factor for some ocular injuries. Occupant height was not a significant factor. National statistics confirm that air bags reduce fatalities in motor vehicle accidents. However, children sitting in the front seat without a seat belt and infants in passenger-side rear-facing car seats are at risk for fatal injury. CONCLUSION: Air bags combined with seat belts are an effective means of reducing injury and death in adults during motor vehicle accidents. However, this study has documented a wide variety of ocular injuries associated with air bag deployment. It is hoped that researchers can develop modifications that continue to save lives while minimizing additional harm. (+info)
Localization of myocilin/trabecular meshwork--inducible glucocorticoid response protein in the human eye.
(19/421)
PURPOSE: To study distribution and cellular localization of myocilin/trabecular meshwork-inducible glucocorticoid response protein (TIGR) in the human eye. METHODS: A peptide antibody against a portion of the myosin-like domain of myocilin/TIGR was developed. Different ocular tissues from three human donors were investigated by one- and two-dimensional gel electrophoresis and Western blot analysis. Immunohistochemistry was performed on 25 human eyes enucleated because of posterior choroidal melanoma and on 7 normal human donor eyes. RESULTS: By Western blot analysis, a band at approximately 57 kDa was visualized in cornea, trabecular meshwork, lamina cribrosa, optic nerve, retina, iris, ciliary body, and vitreous humor. By immunohistochemistry, immunoreactivity for myocilin/TIGR was observed in cells of the corneal epi- and endothelium and extracellularly in the corneal stroma and sclera. In the trabecular meshwork, cells of the uveal and corneoscleral meshwork were stained, as was the cribriform area directly adjacent to Schlemm's canal. Positive staining was seen in cells of the ciliary epithelium, ciliary muscle, lens epithelium, and in stromal and smooth muscle cells of the iris. Throughout the entire vitreous body, fine filamentous material was positively labeled. In the retina, staining was seen along the outer surface of rods and cones, in neurons of the inner and outer nuclear layer, and in the axons of optic nerve ganglion cells. Optic nerve axons were stained in the prelaminar, laminar, and postlaminar parts of the nerve. In the region of the lamina cribrosa, astrocytes in the glial columns and cribriform plates were positively labeled. CONCLUSIONS: Myocilin TIGR is expressed in almost every ocular tissue. Depending on the respective tissue, it is observed extra- or intracellularly. The presence of myocilin/TIGR in optic nerve axons and lamina cribrosa astrocytes indicates that the trabecular meshwork might not be the only target of abnormal myocilin/TIGR in GLC1A-linked open-angle glaucoma. (+info)
Axenfeld-Rieger syndrome resulting from mutation of the FKHL7 gene on chromosome 6p25.
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Mutations in the forkhead-like 7 (FKHL7) gene have been recently shown to cause juvenile glaucoma and anterior segment anomalies. We report on a three-generation family with Axenfeld-Rieger syndrome (ARS), harboring an alteration in the FKHL7 gene. Genetic linkage analyses excluded the ARS phenotype from chromosomes 4q25 and 13q14, the locations of the PITX2 and RIEG2 loci, respectively. Evidence of linkage was observed with markers at 6p25, near the FKHL7 gene. Direct sequencing of FKHL7 detected a C67T mutation that segregated with the ARS phenotype in this family, but was not detected in over 80 control chromosomes. This mutation is predicted to cause a nonsense mutation of the FKHL7 protein (Gln23Stop) upstream of the forkhead DNA-binding domain, and thus to generate a truncated FKHL7 protein product. This discovery broadly implicates FKHL7 in ocular, craniofacial, dental, and umbilical development. (+info)
Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development.
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Anterior segment developmental disorders, including Axenfeld-Rieger anomaly (ARA), variably associate with harmfully elevated intraocular pressure (IOP), which causes glaucoma. Clinically observed dysgenesis does not correlate with IOP, however, and the etiology of glaucoma development is not understood. The forkhead transcription factor genes Foxc1 (formerly Mf1 ) and Foxc2 (formerly Mfh1 ) are expressed in the mesenchyme from which the ocular drainage structures derive. Mutations in the human homolog of Foxc1, FKHL7, cause dominant anterior segment defects and glaucoma in various families. We show that Foxc1 (+/-)mice have anterior segment abnormalities similar to those reported in human patients. These abnormalities include small or absent Schlemm's canal, aberrantly developed trabecular meshwork, iris hypoplasia, severely eccentric pupils and displaced Schwalbe's line. The penetrance of clinically obvious abnormalities varies with genetic background. In some affected eyes, collagen bundles were half normal diameter, or collagen and elastic tissue were very sparse. Thus, abnormalities in extracellular matrix synthesis or organization may contribute to development of the ocular phenotypes. Despite the abnormalities in ocular drainage structures in Foxc1 (+/-)mice, IOP was normal in almost all mice analyzed, on all genetic backgrounds and at all ages. Similar abnormalities were found in Foxc2 (+/-)mice, but no disease-associated mutations were identified in the human homolog FKHL14 in 32 ARA patients. Foxc1 (+/-)and Foxc2 (+/-)mice are useful models for studying anterior segment development and its anomalies, and may allow identification of genes that interact with Foxc1 and Foxc2 (or FKHL7 and FKHL14 ) to produce a phenotype with elevated IOP and glaucoma. (+info)
Investigation of beta defensin gene expression in the ocular anterior segment by semiquantitative RT-PCR.
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AIM: To determine if beta defensins are expressed in the anterior segment of the eye and to determine the temporal pattern of expression using a real time semiquantitative reverse transcription polymerase chain reaction (RT-PCR). METHODS: Ocular tissue (corneal epithelium, conjunctiva, iris, and lens capsule) was collected from 23 patients undergoing surgery. Serial corneal or conjunctival impression cytology was performed on a separate group of 10 patients undergoing corneal tunnel phacoemulsification or trabeculectomy. The samples were analysed for beta defensin mRNA by semiquantitative RT-PCR and the mRNA standardised for cell numbers. RESULTS: RT-PCR amplified beta defensin 1 mRNA from all lens capsule (six) and corneal (five) samples and all but one of the conjunctival (six) and iris samples (six). beta Defensin 2 mRNA was amplified from three of five corneal, two of six conjunctival, and none of the iris or capsule samples. The impression cytology samples demonstrated a decline in defensin expression over the three time points studied. There were no false positive results from either the no-RT or negative control samples. CONCLUSIONS: This preliminary study confirms that natural antibacterial peptides are expressed in the anterior segment of the eye. There appears to be a pattern to the expression with inducible beta defensin 2 not expressed intraocularly and higher levels of beta defensin 1 than beta defensin 2 expressed in extraocular tissue. The implication is that beta defensin 1 is constitutively produced in ocular tissues and represents a key component of the innate immune system. (+info)
Distribution of glucocorticoid and mineralocorticoid receptors and 11beta-hydroxysteroid dehydrogenases in human and rat ocular tissues.
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PURPOSE: The administration of glucocorticoids as topical or systemic medications may lead to the development of ocular hypertension through the induction of morphologic and biochemical changes in the trabecular meshwork leading to a reduction in the facility of aqueous outflow. Glucocorticoids exert their physiological effects by binding to and activating glucocorticoid and mineralocorticoid receptors. The activity of glucocorticoids is critically regulated at a prereceptor level by the two isozymes of 11beta-hydroxysteroid dehydrogenase. The purpose of this study was to determine the distribution of glucocorticoid target receptors and the isozymes of 11beta-hydroxysteroid dehydrogenase (11 beta-HSD) that regulate the activity of glucocorticoids at a prereceptor level in human and rat ocular tissues. METHODS: Horizontal sections of normal adult human and rat eyes were cut and hybridized with 35S-labeled cRNA probes specific for the glucocorticoid receptor, mineralocorticoid receptor, and 11beta-HSD types 1 and 2 using in situ hybridization. Immunohistochemical analysis of glucocorticoid and mineralocorticoid receptors using monoclonal antibodies was carried out on rat eye tissue sections. Whole rat eyes were homogenized and the activity of 11beta-HSD types 1 and 2 in the eye assessed as the percentage conversion of tritiated corticosterone to tritiated 11-dehydrocortico-sterone when corticosterone was added to the homogenate. RESULTS: In the rat ocular tissues mRNAs encoding glucocorticoid receptor, mineralocorticoid receptor, and 11beta-HSD types 1 and 2 were detected in nonpigmented ciliary epithelium, trabecular meshwork, corneal epithelium and endothelium, and anterior lens epithelium. Immunohistochemistry confirmed the presence of glucocorticoid and mineralocorticoid receptors at these sites. Activity of both isozymes of 11beta-HSD was demonstrated in homogenized rat eyes (percentage conversion of tritiated corticosterone to 11-dehydrocorticosterone; mean +/- SD, 11beta-HSD 1 = 15% +/- 5.3%, 11beta-HSD 2 = 7.9% +/- 2.8%). In both human and rat eyes, expression of mRNAs encoding glucocorticoid receptor and 11beta-HSD type 1 was high in the trabecular meshwork and lens epithelium, whereas expression of mRNAs encoding the mineralocorticoid receptor and 11beta-HSD type 2 was high in nonpigmented ciliary epithelium and corneal epithelium and endothelium. CONCLUSIONS: Glucocorticoid target receptors and the enzymes regulating glucocorticoid activity at these receptors are present in mammalian ocular tissues, which regulate aqueous humor formation and outflow. Alteration in the number or affinity of receptors or in the activity of regulatory enzymes may alter the susceptibility of certain individuals to the effects of glucocorticoids on intraocular pressure. (+info)
Direct effects of muscarinic agents on the outflow pathways in human eyes.
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PURPOSE: Recent studies demonstrating the presence of muscarinic receptors and contractile-like cells in the trabecular meshwork tissue and/or cell cultures from human eyes suggest the possibility that there may be a direct effect of muscarinic agonists on outflow facility. The present studies were conducted to determine whether muscarinic agonists could change outflow facility in perfused human ocular anterior segments, which lack an intact ciliary muscle. METHODS: Human eyes were dissected and perfused according to previously described methods. A steady state baseline facility was established for 90 minutes, after which up to four sequential concentrations ranging from 10(-9) to 10(-3) M of pilocarpine, aceclidine, or carbachol were added to the perfusion medium. In other studies, 10(-6) M atropine was perfused alone followed by 10(-7) M carbachol with 10(-6) M atropine, whereas fellow control eyes received carbachol alone. Outflow facility was measured for 60 minutes after each drug addition. The outflow facility measurement in each eye after drug administration was compared with the baseline measurement. RESULTS: Outflow facility increased from baseline facility in eyes treated with pilocarpine, aceclidine, or carbachol at lower concentrations (10(-9) to 10(-6) M) but remained unchanged at higher concentrations (10(-4) to 10(-2) M). The effects of carbachol at 10(-7) M were completely blocked by atropine. CONCLUSIONS: Muscarinic agonists increase outflow facility in human eyes by a direct stimulation of the outflow tissues in the absence of an intact ciliary muscle. This effect is biphasic, occurring at concentrations of 10(-6) M and lower with no effect at higher concentrations. (+info)