The Outflow Pathway: A Tissue With Morphological and Functional Unity

Saccà, Sergio Claudio; Gandolfi, Stefano; Bagnis, Alessandro; Manni, Gianluca; Damonte, Gianluca; Traverso, Carlo Enrico; Izzotti, Alberto

doi:10.1002/jcp.25305

Cited by 81 publications

(74 citation statements)

References 239 publications

(291 reference statements)

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“…Cellular responses to physiological cues including cytokines, growth factors, steroids, miRNAs, ECM, mechanical stretch and reactive oxidants, have been demonstrated to influence AH outflow through the conventional pathway (Clark and Wordinger, 2009; Gabelt and Kaufman, 2005; Gagen et al, 2014; Gonzalez et al, 2014; Keller et al, 2009; Rao and Epstein, 2007; Sacca et al, 2016; Wiederholt et al, 2000). At the physiological level, cellular contraction/relaxation, permeability, cell stiffness, phagocytosis, ECM remodeling, cell survival and anti-oxidative activities are some of the cellular activities recognized to be important for maintaining homeostasis of AH outflow through the conventional pathway (Alvarado et al, 1981; Gabelt and Kaufman, 2005; Rao and Epstein, 2007; Sacca et al, 2016; Stamer and Acott, 2012; Wiederholt et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…At the physiological level, cellular contraction/relaxation, permeability, cell stiffness, phagocytosis, ECM remodeling, cell survival and anti-oxidative activities are some of the cellular activities recognized to be important for maintaining homeostasis of AH outflow through the conventional pathway (Alvarado et al, 1981; Gabelt and Kaufman, 2005; Rao and Epstein, 2007; Sacca et al, 2016; Stamer and Acott, 2012; Wiederholt et al, 2000). Despite continued efforts however, we have yet to identify the definitive molecular pathways that serve as key determinants of trabecular AH outflow homeostasis, the disruption or impairment of which underlies increased resistance to AH outflow and eventually leads to elevated IOP in glaucoma patients (Stamer and Acott, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Rao

Pattabiraman

Kopczynski

2017

Experimental Eye Research

142

166

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Glaucoma is a leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is considered to be a predominant risk factor for primary open angle glaucoma, the most prevalent form of glaucoma. Although the etiological mechanisms responsible for increased IOP are not completely clear, impairment in aqueous humor (AH) drainage through the conventional or trabecular pathway is recognized to be a primary cause in glaucoma patients. Importantly, lowering of IOP has been demonstrated to reduce progression of vision loss and is a mainstay of treatment for all types of glaucoma. Currently however, there are limited therapeutic options available for lowering IOP especially as it relates to enhancement of AH outflow through the trabecular pathway. Towards addressing this challenge, bench and bedside research conducted over the course of the last decade and a half has identified the significance of inhibiting Rho kinase for lowering IOP. Rho kinase is a downstream effector of Rho GTPase signaling that regulates actomyosin dynamics in numerous cell types. Studies from several laboratories have demonstrated that inhibition of Rho kinase lowers IOP via relaxation of the trabecular meshwork which enhances AH outflow. By contrast, activation of Rho GTPase/Rho kinase signaling in the trabecular outflow pathway increases IOP by altering the contractile, cell adhesive and permeability barrier characteristics of the trabecular meshwork and Schlemm’s canal tissues, and by influencing extracellular matrix production and fibrotic activity. This article, written in honor of the late David Epstein, MD, summarizes findings from both basic and clinical studies that have been instrumental for recognition of the importance of the Rho/Rho kinase signaling pathway in regulation of AH outflow, and in the development of Rho kinase inhibitors as promising IOP- lowering agents for glaucoma treatment.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Rao

Pattabiraman

Kopczynski

2017

Experimental Eye Research

142

166

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“…Failure to maintain a normal cytoskeleton and homeostasis of aqueous outflow can cause ocular hypertension 1 . For instance, pigment dispersion 3 and corticosteroids can alter the actin cytoskeleton and cause TM cell contraction resulting in an elevation of intraocular pressure (IOP) 3,4 . Conversely, relaxing the cytoskeleton, for instance by using a Rho kinase inhibitor, can reverse these effects 5,6 .…”

Section: Introductionmentioning

confidence: 99%

Intraocular pressure elevation precedes a phagocytosis decline in a model of pigmentary glaucoma

et al. 2018

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Outflow regulation and phagocytosis are key functions of the Background: trabecular meshwork (TM), but it is not clear how the two are related in secondary open angle glaucomas characterized by an increased particle load. We hypothesized that diminished TM phagocytosis is not the primary cause of early ocular hypertension and recreated pigment dispersion in a porcine ex vivo model.Sixteen porcine anterior chamber cultures received a continuous Methods: infusion of pigment granules (Pg), while 16 additional anterior chambers served as controls (C). Pressure transducers recorded the intraocular pressure (IOP). The phagocytic capacity of the trabecular meshwork was determined by fluorescent microspheres.The baseline IOPs in Pg and C were similar ( =0.82). A significant Results: P IOP elevation occurred in Pg at 48, 120, and 180 hours (all <0.01, compared P to baseline). The pigment did not cause a reduction in TM phagocytosis at 48 hours, when the earliest IOP elevation occurred, but at 120 hours onward (P =0.001 compared to C). This reduction did not result in an additional IOP increase at 120 or 180 hours compared to the first IOP elevation at 48 hours (P >0.05).In this porcine model of pigmentary glaucoma, an IOP elevation Conclusions: occurs much earlier than when phagocytosis fails, suggesting that two separate mechanisms might be at work.

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“…Trabecular meshwork failure can lead to the occurrence of cell decay, reduction of outflow, and eventually increased IOP. 2 Thus, current treatments are focused mainly on lowering IOP. 3 Better understanding of the mechanisms underlying TM failure could potentially promote clinical applications toward efficient treatments.…”

mentioning

confidence: 99%

“…High IOP observed in glaucoma frequently is contributed by failure of the trabecular meshwork (TM). 2 The aqueous humor normally flows through the TM, from the anterior chamber to Schlemm's canal. Trabecular meshwork failure can lead to the occurrence of cell decay, reduction of outflow, and eventually increased IOP.…”

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confidence: 99%

Curcumin Protects Trabecular Meshwork Cells From Oxidative Stress

Lin

2016

Invest. Ophthalmol. Vis. Sci.

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Citation: Lin C, Wu X. Curcumin protects trabecular meshwork cells from oxidative stress. Invest Ophthalmol Vis Sci. 2016;57:4327-4332. DOI:10.1167/iovs.16-19883 PURPOSE. Glaucoma is closely linked with oxidative stress and inflammation, and difficult to treat. Its occurrence frequently is contributed by the failure of the trabecular meshwork (TM). Curcumin is known as an antioxidative and anti-inflammatory substance, possessing the potential to treat glaucoma. METHODS.Using TM cells as the in vitro model system, we investigated the effects of curcumin on oxidative stress-induced markers for TM impairments, including cell death, production of intracellular reactive oxygen species (iROS), induction of proinflammatory proteins, activation of senescence marker, accumulation of carbonylated proteins, and apoptotic cell numbers. RESULTS.Curcumin treatment protected TM cells against oxidative stress-induced cell death. Curcumin treatment at concentrations between 1 and 20 lM reduced the production of iROS in H 2 O 2 -exposed TM cells in a dose-dependent manner. Further studies demonstrated that curcumin treatment (20 lM) significantly inhibited proinflammatory factors, including IL-6, ELAM-1, IL-1a, and IL-8, whereas it decreased activities of senescence marker SA-b-gal, and lowered levels of carbonylated proteins and apoptotic cell numbers.CONCLUSIONS. Curcumin is capable of protecting TM cells against oxidative stress, shedding new light on potential treatment for glaucoma.

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The Outflow Pathway: A Tissue With Morphological and Functional Unity

Cited by 81 publications

References 239 publications

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Intraocular pressure elevation precedes a phagocytosis decline in a model of pigmentary glaucoma

Curcumin Protects Trabecular Meshwork Cells From Oxidative Stress

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