Effects of TGF- 2 in Perfused Human Eyes

Gottanka, Johannes; Chan, Darren; Eichhorn, Michael; Lütjen–Drecoll, Elke; Cr, Ethier

doi:10.1167/iovs.03-0796

Cited by 239 publications

(199 citation statements)

References 10 publications

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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%

“…(Parks and Mecham 1998) These stimuli include TNFα, IL-1α, TGFβ, dexamethasone, elevated pressure, and/or mechanical stretch. (Samples et al 1993;Clark et al 1995b;Alexander et al 1998;Bradley et al 1998;Bradley et al 2000;Bradley et al 2001;Gottanka et al 2004;Chen et al 2005;Clark et al 2005;Vittal et al 2005;Fleenor et al 2006;Kelley et al 2007) The process of ECM turnover is a concerted and highly coordinated program of degradation and biosynthetic replacement of specific ECM components. IOP homeostasis appears to be maintained, at lease in part by ECM turnover triggered in response to pressure changes or mechanical stretch or distortion, sensed by cells within the JCT.…”

Section: Ecm Turnover and Outflow Resistancementioning

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). (Zhao et al 2004;Fleenor et al 2006) Earlier, it was shown that TGFβ1 β2, β3 and β5 all increased MMP-3 expression by the TM.…”

Section: Tgfβmentioning

confidence: 99%

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Extracellular matrix in the trabecular meshwork

Acott

Kelley

2008

Experimental Eye Research

417

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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Section: Matricellular Proteinsmentioning

confidence: 99%

Section: Ecm Turnover and Outflow Resistancementioning

confidence: 99%

Section: Tgfβmentioning

confidence: 99%

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Extracellular matrix in the trabecular meshwork

Acott

Kelley

2008

Experimental Eye Research

417

443

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“…Our results are consistent with previous studies showing that TGF-b2 levels are higher in individuals with a glaucoma diagnosis. 9,10,12 These results, together with studies showing that TGF-b2 increases outflow resistance and IOP in ex vivo and in vivo glaucoma models, 15,16 support the idea that elevated levels of TGF-b2 contribute to the development of open-angle glaucoma.…”

mentioning

confidence: 73%

Influence of Race and Age on Aqueous Humor Levels of Transforming Growth Factor-Beta 2 in Glaucomatous and Nonglaucomatous Eyes

Trivedi

Nutaitis

Vroman

et al. 2011

Journal of Ocular Pharmacology and Therapeutics

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Purpose: To evaluate the influence of race and age on aqueous humor levels of transforming growth factor-beta 2 (TGF-b2). Methods: Patients >40 years of age and undergoing cataract or glaucoma surgery without associated significant intraocular pathology were selected for this study. In bilateral cases, only the first operated eye was included for evaluation. At the time of surgery, a small amount of aqueous was withdrawn. The concentration of total TGFb2 was measured by enzyme-linked immunosorbent assay in duplicate by a masked observer. Results: Fifty-five aqueous humor samples were analyzed from subjects with an average age of 68.05 AE 10.94 years. Overall median TGF-b2 concentration was 247.03 pg/mL. The median concentration of TGF-b2 was higher in eyes with glaucoma than in eyes without glaucoma (269.39 vs. 165.56 pg/mL, respectively; P ¼ 0.001). Subgroup analysis found no significant difference between African American and Caucasian American subjects in the nonglaucomatous or glaucomatous subgroups. Age showed positive correlation with TGF-b2 in nonglaucomatous eyes (r 2 ¼ 0.44, P ¼ 0.019). No correlation between age and TGF-b2 was noted in the glaucoma group (r 2 ¼ 0.02, P ¼ 0.343). Conclusion:The aqueous humor concentration of TGF-b2 was significantly higher in eyes with glaucoma than in eyes without glaucoma. No significant difference between the aqueous humor levels of TGF-b2 from African American and Caucasian American subjects could be measured. However, a significant and positive correlation between age and aqueous humor concentration of TGF-b2 in the eyes of nonglaucomatous subjects was measured. These results are consistent with the idea that elevated levels of TGF-b2 within the anterior segment contribute to the development of glaucoma. In addition, the increased risk for developing glaucoma as one ages may in part be related to the rise of this cytokine.

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“…Eyes were stored in moistened chambers at 4°C until use. The perfusion protocol was similar to that described by Johnson and co-workers (Johnson and Tschumper 1987;Johnson and Tschumper 1989;Johnson 1996), with modifications described in detail previously by our group Gottanka et al 2004). Dulbecco's modified eagle medium (DMEM) was used as perfusate to which antibiotics (0.17 mg/ml Gentamycin, 0.25 μg/ml Amphotericin-B, 100 Units/ml Penicillin and 100 μg/ml Streptomycin; all from Sigma, St. Louis, USA), 1% fetal bovine serum (FBS, Sigma, St. Louis, USA) and 250 μg/ml bovine serum albumin (Sigma, St. Louis, USA) were added.…”

Section: Perfusion Studiesmentioning

confidence: 99%

Targeted gene transfer to Schlemm's canal by retroperfusion

Stamer

Chan

Ethier

2007

Experimental Eye Research

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The goal of the present study was to specifically modify protein expression in the resistancegenerating region of the conventional outflow pathway, namely the inner wall of Schlemm's canal (SC) and the juxtacanalicular region of the trabecular meshwork, in perfused human anterior segments. Anterior segments from human cadaveric eyes were prepared for organ culture using standard techniques and were perfused at constant flow while recording pressure. After reaching a stable outflow facility within physiological limits, forward perfusion was stopped and a fluid-tight fence encircling the limbus was installed and filled with media containing an adenovirus encoding the lacZ reporter gene (either 2×10 6 or 6×10 6 PFU/ml). With the limbus submerged, pressure inside the chamber was lowered to −1 mmHg to facilitate reverse perfusion of virus into SC ("retroperfusion"). After 30-60 min at zero pressure (with some mixing), forward perfusion was restarted and continued for 5-7 days, after which anterior segments were fixed and processed for visualization of lacZ activity. Retroperfusion of 9 anterior segments with adenovirus encoding a reporter gene did not appreciably alter baseline outflow facility (0.27 ± 0.05 versus 0.29 ± 0.08 μl/ min/mmHg post-retroperfusion). Gross examination of outflow tissues showed focal distribution of lacZ activity around the circumference of SC, presumably near collector channels. In segments that were sequentially tilted during retroperfusion, the distribution of lacZ activity appeared more uniform. Sagittal histological sections showed lacZ activity in all portions of the conventional drainage tract, particularly cells in the resistance-generating region. Taken together, results demonstrate that candidate protein expression by cells in the resistance-generating region of the conventional drainage pathway can be specifically modified by retroperfusion of adenovirus and examined for effects on outflow facility.

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Effects of TGF- 2 in Perfused Human Eyes

Cited by 239 publications

References 10 publications

Extracellular matrix in the trabecular meshwork

Extracellular matrix in the trabecular meshwork

Influence of Race and Age on Aqueous Humor Levels of Transforming Growth Factor-Beta 2 in Glaucomatous and Nonglaucomatous Eyes

Targeted gene transfer to Schlemm's canal by retroperfusion

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