Aqueous Humor in Glaucomatous Eyes Contains an Increased Level of TGF-β2

Tripathi, Ramesh C.; Li, Junping; Chan, WaiFong A.; Tripathi, Brenda J.

doi:10.1006/exer.1994.1158

Cited by 503 publications

(378 citation statements)

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“…28 The TGF-b antisense OGN would be expected to have maximal effects on local cellular production of TGF-b at the filtration wound site and not in aqueous which is known to contain high concentrations of TGF-b2 protein in association with glaucoma and intraocular fibrosis. 20,[44][45][46] Aqueous TGF-b2 is produced by cells within the eye, ie in the iris, ciliary body 47 and trabecular meshwork. 48 As application of the TGF-b2 antisense OGN subconjunctivally in this rabbit study is external to the eye, it cannot directly suppress intraocular production of TGF-b2, so we can only postulate that it may reduce aqueous TGF-b2 by interfering with the TGF-b2 autoinduction pathway from the cells within the eye.…”

Section: Discussionmentioning

confidence: 99%

Novel antisense oligonucleotides targeting TGF-β inhibit in vivo scarring and improve surgical outcome

Cordeiro¹,

Mead²,

Ali

et al. 2003

Gene Ther

158

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The scarring response is an important factor in many diseases throughout the body. In addition, it is a major problem in influencing results of surgery. In the eye, for example, post-operative scarring can determine the outcome of surgery. This is particularly the case in the blinding disease glaucoma, where several anti-scarring regimens are currently used to improve glaucoma surgery results, but are of limited use clinically because of severe complications. We have recently identified transforming growth factor-b (TGF-b) as a target for post-operative anti-scarring therapy in glaucoma, and now report the first study of novel secondgeneration antisense phosphorothioate oligonucleotides against TGF-b in vivo. Single applications of a TGF-b OGN at the time of surgery in two different animal models closely related to the surgical procedure performed in glaucoma patients, significantly reduced post-operative scarring (Po0.05) and improved surgical outcome. Our findings suggest that TGF-b antisense oligonucleotides have potential as a new therapy for reducing post-surgical scarring. Its long-lasting effects after only a single administration at the time of surgery make it particularly attractive clinically. Furthermore, although we have shown this agent to be useful in the eye, it could have widespread applications anywhere in the body where the wound-healing response requires modulation.

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Section: Discussionmentioning

confidence: 99%

Novel antisense oligonucleotides targeting TGF-β inhibit in vivo scarring and improve surgical outcome

Cordeiro¹,

Mead²,

Ali

et al. 2003

Gene Ther

158

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“…(Crawford et al 1998) Since TGFβ is thought to be of significance in affecting the normal and glaucomatous ECMs of the outflow pathway and has been shown to modify outflow facility, this may be of considerable importance. (Tripathi, RC et al 1994;Welge-Lussen et al 1999;Li et al 2000;Welge-Lussen et al 2000;Lutjen-Drecoll and Rohen 2001;Gottanka et al 2004) Immunostaining for thrombospondin 1 is observed throughout the TM, with the greatest density in the JCT region. (Flugel-Koch et al 2004) Tenascin C or hexabrachion is another matricellular protein expressed in the TM.…”

Section: Matricellular Proteinsmentioning

confidence: 99%

“…(Tripathi, RC et al 1994) TGFβ2 perfusion reduces outflow facility and is generally thought to increase ECM production. (Gottanka et al 2004;Fleenor et al 2006) In TM cells, a number of ECM genes are modulated by TGFβ1 and/or TGFβ2 (Table 3).…”

Section: Tgfβmentioning

confidence: 99%

Extracellular matrix in the trabecular meshwork

Acott

Kelley

2008

Experimental Eye Research

419

443

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The extracellular matrix (ECM) of the trabecular meshwork (TM) is thought to be important in regulating intraocular pressure (IOP) in both normal and glaucomatous eyes. IOP is regulated primarily by a fluid resistance to aqueous humor outflow. However, neither the exact site nor the identity of the normal resistance to aqueous humor outflow has been established. Whether the site and nature of the increased outflow resistance, which is associated with open-angle glaucoma, is the same or different from the normal resistance is also unclear.The ECMs of the TM beams, juxtacanalicular region (JCT) and Schlemm's canal (SC) inner wall are comprised of fibrillar and non-fibrillar collagens, elastin-containing microfibrils, matricellular and structural organizing proteins, glycosaminoglycans (GAGs) and proteoglycans. Both basement membranes and stromal ECM are present in the TM beams and JCT region. Cell adhesion proteins, cell surface ECM receptors and associated binding proteins are also present in the beams, JCT and SC inner wall region.The outflow pathway ECM is relatively dynamic, undergoing constant turnover and remodeling. Regulated changes in enzymes responsible for ECM degradation and biosynthetic replacement are observed. IOP homeostasis, triggered by pressure changes or mechanical stretching of the TM, appears to involve ECM turnover. Several cytokines, growth factors and drugs, which affect the outflow resistance, change ECM component expression, mRNA alternative splicing, cellular cytoskeletal organization or all of these. Changes in ECM associated with open-angle glaucoma have been identified.

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“…All these factors might play a role in the increase in MYOC/TIGR expression in eyes with POAG. Topical treatment with dexamethasone can increase IOP (Armaly 1963a,b;Armaly 1965;Becker 1965), transforming growth factor-b is elevated in the aqueous humor of patients with POAG (Tripathi et al 1994), and an increase in IOP should cause increased mechanical tension and stretch in the trabecular meshwork. We hypothesize that the expression of MYOC/TIGR in the eye, and its increase in POAG is regulated at the level of transcription.…”

Section: Introductionmentioning

confidence: 99%

Regulation of human myocilin/TIGR gene transcription in trabecular meshwork cells and astrocytes: role of upstream stimulatory factor

et al. 2000

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Background: Mutations in the myocilin (MYOC)/ TIGR gene are responsible for autosomal-dominant juvenile primary open-angle glaucoma (POAG). In patients with non-autosomal-dominant POAG, such mutations are rare, but the expression of MYOC/TIGR in the trabecular meshwork (TM) of the eye is considerably higher than in normals. We performed transfection, DNAse I footprinting, mutagenesis and electrophoretic mobility shift assays (EMSA) to identify elements responsible for the basal transcription of MYOC/TIGR in TM cells and astrocytes.

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Aqueous Humor in Glaucomatous Eyes Contains an Increased Level of TGF-β2

Cited by 503 publications

References 0 publications

Novel antisense oligonucleotides targeting TGF-β inhibit in vivo scarring and improve surgical outcome

Novel antisense oligonucleotides targeting TGF-β inhibit in vivo scarring and improve surgical outcome

Extracellular matrix in the trabecular meshwork

Regulation of human myocilin/TIGR gene transcription in trabecular meshwork cells and astrocytes: role of upstream stimulatory factor

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