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The trabecular meshwork in acute and chronic angle closure glaucoma.  [cached]
Sihota R,Lakshmaiah N,Walia K,Sharma S
Indian Journal of Ophthalmology , 2001,
Abstract: PURPOSE: To determine the effect of acute and chronic primary angle closure glaucoma (PACG) on the trabecular meshwork. METHODS: Trabecular specimens of 16 consecutive patients with primary angle closure glaucoma (PACG)--6 acute PACG eyes, and 10 chronic PACG eyes without an acute attack--were studied by light and electron microscopy. RESULTS: Acute PACG: The trabecular meshwork revealed a generalised oedema and an accumulation of pigment in the widened trabecular spaces and Schlemm′s canal. Attenuated trabecular endothelial cells appeared to be devoid of subcellular components. Chronic PACG: In chronic PACG eyes the trabecular architecture had lost its regular arrangement, with fewer and narrower trabecular spaces and fusion of the trabecular beams in areas. There were numerous electron-dense bodies in the trabecular tissues, both within the trabecular beams and in the extracellular spaces, which had a banded fibrillar structure. An overall loss of endothelial cells was noted; the remaining cells were crowded together and were polymorphic. Melanin pigment was present both within the stroma and in the endothelial cells. CONCLUSIONS: Pigment accumulation in the trabecular spaces and within the cells and a noninflammatory degeneration appeared to be the primary changes in the trabecular meshwork after acute angle closure glaucoma. In chronic PACG eyes, there was evidence of loss of endothelial cells and reactive repair processes. These changes were present in areas away from visible peripheral anterior synechiae. A gonioscopic evaluation of the extent of peripheral anterior synechiae alone may not reflect the extent of trabecular meshwork damage in acute and chronic PACG. Patients experiencing an acute attack of PACG require a long-term follow up, because the intraocular pressure (IOP) may rise later, due to ongoing changes compromising the outflow facility, or due to the effects of aging in the trabecular meshwork.
Trabecular Meshwork Gene Expression after Selective Laser Trabeculoplasty  [PDF]
Alberto Izzotti,Mariagrazia Longobardi,Cristina Cartiglia,Federico Rathschuler,Sergio Claudio Saccà
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020110
Abstract: Trabecular meshwork and Schlemm's canal are the tissues appointed to modulate the aqueous humour outflow from the anterior chamber. The impairment of their functions drives to an intraocular pressure increase. The selective laser trabeculoplasty is a laser therapy of the trabecular meshwork able to decrease intraocular pressure. The exact response mechanism to this treatment has not been clearly delineated yet. The herein presented study is aimed at studying the gene expression changes induced in trabecular meshwork cells by selective laser trabeculoplasty (SLT) in order to better understand the mechanisms subtending its efficacy.
Oxidative Damage and Autophagy in the Human Trabecular Meshwork as Related with Ageing  [PDF]
Alessandra Pulliero, Anke Seydel, Anna Camoirano, Sergio Claudio Saccà, Marco Sandri, Alberto Izzotti
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098106
Abstract: Autophagy is an intracellular lysosomal degradation process induced under stress conditions. Autophagy also plays a major role in ocular patho-physiology. Molecular aging does occur in the trabecular meshwork, the main regulator of aqueous humor outflow, and trabecular meshwork senescence is accompanied by increased oxidative stress. However, the role of autophagy in trabecular meshwork patho-physiology has not yet been examined in vivo in human ocular tissues. The purpose of the herein presented study is to evaluate autophagy occurrence in ex-vivo collected human trabecular meshwork specimens and to evaluate the relationship between autophagy, oxidative stress, and aging in this tissue. Fresh trabecular meshwork specimens were collected from 28 healthy corneal donors devoid of ocular pathologies and oxidative DNA damage, and LC3 and p62 protein expression analyzed. In a subset of 10 subjects, further to trabecular meshwork proteins, the amounts of cathepesin L and ubiquitin was analyzed by antibody microarray in aqueous humor. Obtained results demonstrate that autophagy activation, measured by LC3II/I ratio, is related with. oxidative damage occurrence during aging in human trabecular meshwork. The expression of autophagy marker p62 was lower in subjects older than 60 years as compared to younger subjects. These findings reflect the occurrence of an agedependent increase in the autophagy as occurring in the trabecular meshwork. Furthermore, we showed that aging promotes trabecular-meshwork senescence due to increased oxidative stress paralleled by autophagy increase. Indeed, both oxidative DNA damage and autophagy were more abundant in subjects older than 60 years. These findings shed new light on the role of oxidative damage and autophagy during trabecular-meshwork aging.
Inhibition of Hyaluronan Synthesis Reduces Versican and Fibronectin Levels in Trabecular Meshwork Cells  [PDF]
Kate E. Keller, Ying Ying Sun, Janice A. Vranka, Lauren Hayashi, Ted S. Acott
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048523
Abstract: Hyaluronan (HA) is a major component of the extracellular matrix (ECM) and is synthesized by three HA synthases (HAS). Similarities between the HAS2 knockout mouse and the hdf mutant mouse, which has a mutation in the versican gene, suggest that HA and versican expression may be linked. In this study, the relationship between HA synthesis and levels of versican, fibronectin and several other ECM components in trabecular meshwork cells from the anterior segment of the eye was investigated. HA synthesis was inhibited using 4-methylumbelliferone (4MU), or reduced by RNAi silencing of each individual HAS gene. Quantitative RT-PCR and immunoblotting demonstrated a reduction in mRNA and protein levels of versican and fibronectin. Hyaluronidase treatment also reduced versican and fibronectin levels. These effects could not be reversed by addition of excess glucose or glucosamine or exogenous HA to the culture medium. CD44, tenascin C and fibrillin-1 mRNA levels were reduced by 4MU treatment, but SPARC and CSPG6 mRNA levels were unaffected. Immunostaining of trabecular meshwork tissue after exposure to 4MU showed an altered localization pattern of HA-binding protein, versican and fibronectin. Reduction of versican by RNAi silencing did not affect HA concentration as assessed by ELISA. Together, these data imply that HA concentration affects synthesis of certain ECM components. Since precise regulation of the trabecular meshwork ECM composition and organization is required to maintain the aqueous humor outflow resistance and intraocular pressure homeostasis in the eye, coordinated coupling of HA levels and several of its ECM binding partners should facilitate this process.
The mouse anterior chamber angle and trabecular meshwork develop without cell death
Richard S Smith, Adriana Zabaleta, Olga V Savinova, Simon WM John
BMC Developmental Biology , 2001, DOI: 10.1186/1471-213x-1-3
Abstract: The mouse angle structures and developmental sequence are similar to those in humans. Cell death was not detectable during the period of trabecular channel and beam formation.These results support morphogenic mechanisms involving organization of cellular and extracellular matrix components without cell death or atrophy.Abnormal anterior segment development is often associated with elevated intraocular pressure (IOP), an important risk factor for the blinding disease glaucoma [1]. The anterior segment of the eye is filled with a clear fluid known as the aqueous humor or aqueous. Maintenance of IOP is dependent on a balance between aqueous formation and aqueous outflow. The primary source of aqueous is blood flowing through the arteries of the ciliary body [2]. The aqueous is secreted by the ciliary body into the posterior chamber between the iris and lens. It then flows into the anterior chamber, the space between the cornea and iris, before draining from the eye at the iridocorneal junction [3]. The iridocorneal junction is located in a region known as the iridocorneal angle because of the aqueous filled angular recess between the iris root and cornea. One drainage route consists of a trabecular meshwork (TM) of connective tissue covered by endothelial like trabecular cells and a Schlemm's canal (SC). The aqueous percolates through channels or intertrabecular spaces in the TM before entering SC. The fluid collected by SC drains into aqueous veins that connect to the canal. This route is generally accepted to be the major drainage pathway for the aqueous [3]. Egress via the loose connective tissue meshwork and blood vessels of the uvea (choroid, iris and ciliary body) and the outer wall of the eye (sclera) also contributes to aqueous drainage [3, 4]. Primary access of aqueous to the uveoscleral route is likely deep in the angle recess at the iridocorneal junction. The resistance to aqueous flow presented by the tissues of the TM, SC, and likely uvea and sclera are im
Synthesis and secretion of transferrin by a bovine trabecular meshwork cell line
Bertazolli-Filho, R.;Laicine, E.M.;Haddad, A.;
Brazilian Journal of Medical and Biological Research , 2007, DOI: 10.1590/S0100-879X2006005000158
Abstract: the trabecular meshwork (tm) is the main outflow pathway in the mammalian eye. oxidative damage to tm cells has been suggested to be an important cause of impairment of tm functions, leading to deficient drainage of aqueous humor, with deleterious consequences to the eye. transferrin, a metalloprotein involved in iron transport, has been characterized as an intrinsic eye protein. since transferrin is implicated in the control of oxidative stress, the objective of the present study was to determine if a bovine tm cell line (ctob) synthesizes and secretes transferrin. the ctob cell line was cultured in the presence of 35s-methionine and the incubation medium was submitted to immunoprecipitation. total rnas from ctob and isolated bovine tm (freshly isolated, incubated or not) were subjected to the reverse transcription-polymerase chain reaction and the amplification products were sequenced. also, both ctob and histological tm preparations were processed for transferrin immunolocalization. a labeled peptide of about 80 kda, the expected size for transferrin, was immunopurified from ctob samples obtained from the incubation assays. the reverse transcription-polymerase chain reaction and sequencing experiments detected the presence of transferrin mrna in ctob and isolated bovine tm. reactivity to antibodies against transferrin was observed both in ctob and tm. the results obtained in all of these experiments indicated that the tm is capable of synthesizing and secreting transferrin. the possible implications for the physiology of the eye are discussed.
TGF-β2-Induced Invadosomes in Human Trabecular Meshwork Cells  [PDF]
Hong Han, Daniel Kampik, Franz Grehn, Günther Schlunck
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0070595
Abstract: Primary open-angle glaucoma (POAG) is a leading cause of blindness due to chronic degeneration of retinal ganglion cells and their optic nerve axons. It is associated with disturbed regulation of intraocular pressure, elevated intraocular levels of TGF-β2, aberrant extracellular matrix (ECM) deposition and increased outflow resistance in the trabecular meshwork (TM). The mechanisms underlying these changes are not fully understood. Cell-matrix interactions have a decisive role in TM maintenance and it has been suggested that TGF-β-induced inhibition of matrix metalloproteases may drive aberrant ECM deposition in POAG. Invadopodia and podosomes (invadosomes) are distinct sites of cell-matrix interaction and localized matrix-metalloprotease (MMP) activity. Here, we report on the effects of TGF-β2 on invadosomes in human trabecular meshwork cells. Human TM (HTM) cells were derived from donor tissue and pretreated with vehicle or TGF-β2 (2 ng/ml) for 3d. Invadosomes were studied in ECM degradation assays, protein expression and MMP-2 activity were assessed by western blot and zymography and ECM protein transcription was detected by RT-qPCR. HTM cells spontaneously formed podosomes and invadopodia as detected by colocalization of Grb2 or Nck1 to sites of gelatinolysis. Pretreatment with TGF-β2 enhanced invadosomal proteolysis and zymographic MMP-2 activity as well as MMP-2, TIMP-2 and PAI-1 levels in HTM cell culture supernatants. Rho-kinase inhibition by H1152 blocked the effects of TGF-β2. Concomitant transcription of fibronectin and collagens-1, -4 and -6 was increased by TGF-β2 and fibrillar fibronectin deposits were observed in areas of invadosomal ECM remodelling. In contrast to a current hypothesis, our data indicate that TGF-β2 induces an active ECM remodelling process in TM cells, characterized by concurrent increases in localized ECM digestion and ECM expression, rather than a mere buildup of material due to a lack of degradation. Invadosomal cell adhesion and signaling may thus have a role in POAG pathophysiology.
Mitochondrial Damage in the Trabecular Meshwork Occurs Only in Primary Open-Angle Glaucoma and in Pseudoexfoliative Glaucoma  [PDF]
Alberto Izzotti,Mariagrazia Longobardi,Cristina Cartiglia,Sergio Claudio Saccà
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014567
Abstract: Open-angle glaucoma appears to be induced by the malfunction of the trabecular meshwork cells due to injury induced by oxidative damage and mitochondrial impairment. Here, we report that, in fact, we have detected mitochondrial damage only in primary open-angle glaucoma and pseudo-exfoliation glaucoma, among several glaucoma types compared.
Progenitors for the Corneal Endothelium and Trabecular Meshwork: A Potential Source for Personalized Stem Cell Therapy in Corneal Endothelial Diseases and Glaucoma
Wing Yan Yu,Carl Sheridan,Ian Grierson,Sharon Mason,Victoria Kearns,Amy Cheuk Yin Lo,David Wong
Journal of Biomedicine and Biotechnology , 2011, DOI: 10.1155/2011/412743
Abstract: Several adult stem cell types have been found in different parts of the eye, including the corneal epithelium, conjunctiva, and retina. In addition to these, there have been accumulating evidence that some stem-like cells reside in the transition area between the peripheral corneal endothelium (CE) and the anterior nonfiltering portion of the trabecular meshwork (TM), which is known as the Schwalbe's Ring region. These stem/progenitor cells may supply new cells for the CE and TM. In fact, the CE and TM share certain similarities in terms of their embryonic origin and proliferative capacity in vivo. In this paper, we discuss the putative stem cell source which has the potential for replacement of lost and nonfunctional cells in CE diseases and glaucoma. The future development of personalized stem cell therapies for the CE and TM may reduce the requirement of corneal grafts and surgical treatments in glaucoma.
Regulation of Trabecular Meshwork Cell Contraction and Intraocular Pressure by miR-200c  [PDF]
Coralia Luna, Guorong Li, Jianyong Huang, Jianming Qiu, Jing Wu, Fan Yuan, David L. Epstein, Pedro Gonzalez
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051688
Abstract: Lowering intraocular pressure (IOP) delays or prevents the loss of vision in primary open-angle glaucoma (POAG) patients with high IOP and in those with normal tension glaucoma showing progression. Abundant evidence demonstrates that inhibition of contractile machinery of the trabecular meshwork cells is an effective method to lower IOP. However, the mechanisms involved in the regulation of trabecular contraction are not well understood. Although microRNAs have been shown to play important roles in the regulation of multiple cellular functions, little is known about their potential involvement in the regulation of IOP. Here, we showed that miR-200c is a direct postranscriptional inhibitor of genes relevant to the physiologic regulation of TM cell contraction including the validated targets Zinc finger E-box binding homeobox 1 and 2 (ZEB1 and ZEB2), and formin homology 2 domain containing 1 (FHOD1), as well as three novel targets: lysophosphatidic acid receptor 1 (LPAR1/EDG2), endothelin A receptor (ETAR), and RhoA kinase (RHOA). Consistently, transfection of TM cells with miR-200c resulted in strong inhibition of contraction in collagen populated gels as well as decreased cell traction forces exerted by individual TM cells. Finally, delivery of miR-200c to the anterior chamber of living rat eyes resulted in a significant decrease in IOP, while inhibition of miR-200c using an adenoviral vector expressing a molecular sponge led to a significant increase in IOP. These results demonstrate for the first time the ability of a miRNA to regulate trabecular contraction and modulate IOP in vivo, making miR-200c a worthy candidate for exploring ways to alter trabecular contractility with therapeutic purposes in glaucoma.
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