Oxidative DNA Damage in the Human Trabecular Meshwork

Saccà, Sergio Claudio; Pascotto, Antonio; Camicione, Paola; Capris, P.; Izzotti, Alberto

doi:10.1001/archopht.123.4.458

Cited by 322 publications

(140 citation statements)

References 28 publications

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“…31 Recent evidence demonstrates that there is extensive oxidative DNA damage involving the trabecular cells of patients with POAG, affecting the filtration zone and inner trabecular meshwork layers. 32 Other studies report that incorporating a specific type of myocilin mutant known to be present in vivo in certain types of open angle glaucoma into TMEs in vitro (that is, Pro370Leu) results in ''killing'' of cultured human TMEs. 33 The demise of TMEs is the result of misfolding, aggregation, and build up of this protein in the endoplasmic reticulum of trabecular cells.…”

Section: Discussionmentioning

confidence: 99%

A new insight into the cellular regulation of aqueous outflow: how trabecular meshwork endothelial cells drive a mechanism that regulates the permeability of Schlemm's canal endothelial cells

Alvarado

Yeh

et al. 2005

British Journal of Ophthalmology

140

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Aim: To test the hypothesis that trabecular meshwork endothelial cells (TMEs) increase the permeability of Schlemm's canal endothelial cells (SCEs) by actively releasing ligands that modulate the barrier properties of SCEs. Methods: The TMEs were first irradiated with a laser light and allowed to condition the medium, which is then added to SCEs. The treatment response is determined by both measuring SCE permeability (flow meters) and the differential expression of genes (Affymetrix chips and quantitative polymerase chain reaction (PCR)). The cytokines secreted by the treated cells were identified using ELISA and the ability of these cytokines to increase permeability is tested directly after their addition to SCEs in perfusion experiments. Results: SCEs exposed to medium conditioned by the light activated TMEs (TME-cm) respond by undergoing a differential expression (DE) of 1120 genes relative to controls. This response is intense relative to a DE of only 12 genes in lasered SCEs. The TME-cm treatment of SCEs increased the SCE permeability fourfold. The role of cytokines in these responses is supported by two findings: adding specific cytokines established to be secreted by lasered TMEs to SCEs increases permeability; and inactivating the TME-cm by boiling or diluting, abrogates these conditioned media permeability effects. Conclusion: These experiments show that TMEs can regulate SCE permeability and that it is likely that TMEs have a major role in the regulation of aqueous outflow. This novel TME driven cellular mechanism has important implications for the pathogenesis of glaucoma and the mechanism of action of laser trabeculoplasty. Ligands identified as regulating SCE permeability have potential use for glaucoma therapy.T he conventional aqueous outflow pathway (CAOP) performs the dual functions of facilitating the egress of aqueous from the anterior chamber of the eye into the lumen of Schlemm's canal and of preventing the reflux of blood from the venous circulation into the anterior chamber.

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Section: Discussionmentioning

confidence: 99%

A new insight into the cellular regulation of aqueous outflow: how trabecular meshwork endothelial cells drive a mechanism that regulates the permeability of Schlemm's canal endothelial cells

Alvarado

Yeh

et al. 2005

British Journal of Ophthalmology

140

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“…Numerous studies have identified oxidative damage as an important event in the pathogenesis of ocular diseases such as macular degeneration (Kinnunen et al, 2011), cataract (Varma et al, 2011), and glaucoma (Abu-Amero et al, 2006; Alvarado et al, 1981; Chang, 2006; Chen and Kadlubar, 2003; Ferreira et al, 2004; Gabelt and Kaufman, 2005; Holekamp et al, 2005; Izzotti et al 2003; Izotti et al, 2006; Izzotti et al, 2009; Kong et al, 2009; Liton et al, 2009; Sacca et al, 2005; Sacca et al, 2007; Sacca and Izzotti, 2008; Shui et al, 2006; Siegfried et al, 2010; Tomarev, 2001; Wang et al, 2001; Zhou and Yue, 1999). Two important hemodynamic parameters of oxygen metabolism include oxygen partial pressure ( p O 2 ) and oxygen saturation of hemoglobin (sO 2 ).…”

Section: Introductionmentioning

confidence: 99%

Photoacoustic tomography imaging and estimation of oxygen saturation of hemoglobin in ocular tissue of rabbits

Hennen

Xing

Shui

et al. 2015

Experimental Eye Research

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This study evaluated in vivo imaging capabilities and safety of qualitative monitoring of oxygen saturation of hemoglobin (sO2) of rabbit ciliary body tissues obtained with acoustic resolution (AR) photoacoustic tomography (PAT). AR PAT was used to collect trans-scleral images from ciliary body vasculature of seven New Zealand White rabbits. The PAT sO2 measurements were obtained under the following conditions: when systemic sO2 as measured by pulse oximetry was between 100% and 99% (level 1); systemic sO2 as measured by pulse oximetry was between 98% and 90% (level 2); and systemic sO2 as measured by pulse oximetry was less than 90% (level 3). Following imaging, histological analysis of ocular tissue was conducted to evaluate for possible structural damage caused by the AR PAT imaging. AR PAT was able to resolve anatomical structures of the anterior segment of the eye, viewed through the cornea or anterior sclera. Histological studies revealed no ocular damage. On average, sO2 values (%) obtained with AR PAT were lower than sO2 values obtained with pulse oximetry (all p<0.001): 86.28±4.16 versus 99.25±0.28, 84.09±1.81 vs. 95.3±2.6, and 64.49±7.27 vs. 71.15±10.21 for levels 1, 2 and 3 respectively. AR PAT imaging modality is capable of qualitative monitoring for deep tissue sO2 in rabbits. Further studies are needed to validate and modify the AR PAT modality specifically for use in human eyes. Having a safe, non-invasive method of in vivo imaging of sO2 in the anterior segment is important to studies evaluating the role of oxidative damage, hypoxia and ischemia in pathogenesis of ocular diseases.

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“…Molecular aging does occur in the trabecular meshwork (TM), the main regulator of aqueous humor outflow [12]. Oxidative damage in TM occur in primary open angle glaucoma [13] and is strictly related with intraocular pressure increase and visual field damage [14]. Indeed, dysfunction of the TM increases the resistance of the outflow pathway and induces an increase in intraocular pressure.…”

Section: Introductionmentioning

confidence: 99%

Oxidative Damage and Autophagy in the Human Trabecular Meshwork as Related with Ageing

et al. 2014

Self Cite

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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.

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Oxidative DNA Damage in the Human Trabecular Meshwork

Cited by 322 publications

References 28 publications

A new insight into the cellular regulation of aqueous outflow: how trabecular meshwork endothelial cells drive a mechanism that regulates the permeability of Schlemm's canal endothelial cells

A new insight into the cellular regulation of aqueous outflow: how trabecular meshwork endothelial cells drive a mechanism that regulates the permeability of Schlemm's canal endothelial cells

Photoacoustic tomography imaging and estimation of oxygen saturation of hemoglobin in ocular tissue of rabbits

Oxidative Damage and Autophagy in the Human Trabecular Meshwork as Related with Ageing

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