scholarly journals Role of MCP-1 and IL-8 in viral anterior uveitis, and contractility and fibrogenic activity of trabecular meshwork cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jiyoung Lee ◽  
Jin A. Choi ◽  
Hyun-hee Ju ◽  
Ju-Eun Kim ◽  
Soon-Young Paik ◽  
...  
Keyword(s):  
Viral Infection ◽  
Aqueous Humor ◽  
Trabecular Meshwork ◽  
Anterior Uveitis ◽  
Rho Gtpase ◽  
Open Angle Glaucoma ◽  
Focal Adhesions ◽  
Aqueous Humor Outflow ◽  
Trabecular Meshwork Cells ◽  
Aqueous Outflow

AbstractThe inflammatory chemokines, monocyte chemoattractant protein (MCP)-1 and IL-8, are produced by normal trabecular meshwork cells (TM) and elevated in the aqueous humor of primary open angle glaucoma (POAG) and hypertensive anterior uveitis associated with viral infection. However, their role in TM cells and aqueous humor outflow remains unclear. Here, we explored the possible involvement of MCP-1 and IL-8 in the physiology of TM cells in the context of aqueous outflow, and the viral anterior uveitis. We found that the stimulation of human TM cells with MCP-1 and IL-8 induced significant increase in the formation of actin stress fibers and focal adhesions, myosin light chain phosphorylation, and the contraction of TM cells. MCP-1 and IL-8 also demonstrated elevation of extracellular matrix proteins, and the migration of TM cells. When TM cells were infected with HSV-1 and CMV virus, there was a significant increase in cytoskeletal contraction and Rho-GTPase activation. Viral infection of TM cells revealed significantly increased expression of MCP-1 and IL-8. Taken together, these results indicate that MCP-1 and IL-8 induce TM cell contractibility, fibrogenic activity, and plasticity, which are presumed to increase resistance to aqueous outflow in viral anterior uveitis and POAG.

scholarly journals Novel molecular insights into RhoA GTPase-induced resistance to aqueous humor outflow through the trabecular meshwork

2008 ◽  
Vol 295 (5) ◽  
pp. C1057-C1070 ◽  
Author(s):  
Min Zhang ◽  
Rupalatha Maddala ◽  
Ponugoti Vasantha Rao
Keyword(s):  
Aqueous Humor ◽  
Trabecular Meshwork ◽  
Rho Gtpase ◽  
Cytoskeletal Proteins ◽  
Fiber Formation ◽  
Aqueous Humor Outflow ◽  
Ecm Proteins ◽  
Rhoa Gtpase ◽  
Cell Adhesive ◽  
Adhesive Interactions

Impaired drainage of aqueous humor through the trabecular meshwork (TM) culminating in increased intraocular pressure is a major risk factor for glaucoma, a leading cause of blindness worldwide. Regulation of aqueous humor drainage through the TM, however, is poorly understood. The role of RhoA GTPase-mediated actomyosin organization, cell adhesive interactions, and gene expression in regulation of aqueous humor outflow was investigated using adenoviral vector-driven expression of constitutively active mutant of RhoA (RhoAV14). Organ-cultured anterior segments from porcine eyes expressing RhoAV14 exhibited significant reduction of aqueous humor outflow. Cultured TM cells expressing RhoAV14 exhibited a pronounced contractile morphology, increased actin stress fibers, and focal adhesions and increased levels of phosphorylated myosin light chain (MLC), collagen IV, fibronectin, and laminin. cDNA microarray analysis of RNA extracted from RhoAV14-expressing human TM cells revealed a significant increase in the expression of genes encoding extracellular matrix (ECM) proteins, cytokines, integrins, cytoskeletal proteins, and signaling proteins. Conversely, various ECM proteins stimulated robust increases in phosphorylation of MLC, paxillin, and focal adhesion kinase and activated Rho GTPase and actin stress fiber formation in TM cells, indicating a potential regulatory feedback interaction between ECM-induced mechanical strain and Rho GTPase-induced isometric tension in TM cells. Collectively, these data demonstrate that sustained activation of Rho GTPase signaling in the aqueous humor outflow pathway increases resistance to aqueous humor outflow through the trabecular pathway by influencing the actomyosin assembly, cell adhesive interactions, and the expression of ECM proteins and cytokines in TM cells.

scholarly journals The role of calcium-independent phospholipase A2γ in modulation of aqueous humor drainage and Ca2+ sensitization of trabecular meshwork contraction

2012 ◽  
Vol 302 (7) ◽  
pp. C979-C991 ◽  
Author(s):  
Padmanabhan P. Pattabiraman ◽  
Fred B. Lih ◽  
Kenneth B. Tomer ◽  
Ponugoti Vasantha Rao
Keyword(s):  
Arachidonic Acid ◽  
Aqueous Humor ◽  
Trabecular Meshwork ◽  
Rho Gtpase ◽  
Focal Adhesions ◽  
Intense Staining ◽  
Outflow Facility ◽  
Bromoenol Lactone ◽  
Mlc Phosphorylation

The contractile and relaxation characteristics of trabecular meshwork (TM) are presumed to influence aqueous humor (AH) drainage and intraocular pressure. The mechanisms underlying regulation of TM cell contractile properties, however, are not well understood. This study investigates the role of calcium-independent phospholipase A2 (iPLA2), which controls eicosanoid synthesis, in regulation of TM cell contraction and AH outflow using mechanism-based isoform specific inhibitors (R)-bromoenol lactone (R-BEL, iPLA2γ specific) and (S)-bromoenol lactone (S-BEL, iPLA2β specific). Immunohistochemical analysis revealed intense staining for both iPLA2β and γ isoforms throughout the TM, juxtacanalicular tissue, and Schlemm's canal of human eye. Inhibition of iPLA2γ by R-BEL or small interfering RNA-mediated silencing of iPLA2γ expression induced dramatic changes in TM cell morphology, and decreased actin stress fibers, focal adhesions, and myosin light-chain (MLC) phosphorylation. AH outflow facility increased progressively and significantly in enucleated porcine eyes perfused with R-BEL. This response was associated with a significant decrease in TM tissue MLC phosphorylation and alterations in the morphology of aqueous plexi in R-BEL-perfused eyes. In contrast, S-BEL did not affect either of these parameters. Additionally, R-BEL-induced cellular relaxation of the TM was associated with a significant decrease in the levels of active Rho GTPase, phospho-MLC phosphatase, phospho-CPI-17, and arachidonic acid. Taken together, these observations demonstrate that iPLA2γ plays a significant and isoform-specific role in regulation of AH outflow facility by altering the contractile characteristics of the TM. The effects of iPLA2γ on TM contractile status appear to involve arachidonic acid and Rho GTPase signaling pathways.

scholarly journals Mechanisms of ATP release by human trabecular meshwork cells, the enabling step in purinergic regulation of aqueous humor outflow

2011 ◽  
Vol 227 (1) ◽  
pp. 172-182 ◽  
Author(s):  
Ang Li ◽  
Chi Ting Leung ◽  
Kim Peterson-Yantorno ◽  
W. Daniel Stamer ◽  
Claire H. Mitchell ◽  
...  
Keyword(s):  
Aqueous Humor ◽  
Trabecular Meshwork ◽  
Atp Release ◽  
Aqueous Humor Outflow ◽  
Trabecular Meshwork Cells

scholarly journals The Effects of Prostaglandin Analogs on Intraocular Pressure in Human Eye for Open Angle Glaucoma

2020 ◽  
Vol 10 (2) ◽  
pp. 176-180
Author(s):  
Shabab Akbar ◽  
Sapna Ratan Shah
Keyword(s):  
Fluid Flow ◽  
Intraocular Pressure ◽  
Aqueous Humor ◽  
Trabecular Meshwork ◽  
Ciliary Body ◽  
Open Angle Glaucoma ◽  
Posterior Chamber ◽  
Open Angle ◽  
Permeable Channel ◽  
Aqueous Outflow

The effects of Prostaglandin Analogs on intraocular pressure and increased aqueous outflow via trabecular meshwork into the schlemm’s canal has been studied in this present research paper. Aqueous humor is an outflow, which flows at the back of the iris in the posterior chamber all the way through the pupil aperture, out into the anterior chamber, and drain from the eye via drainage slope. The eye keeps on making aqueous humor in the ciliary body and it passes through the trabecular meshwork into the scheme of the canal, the key drainage from the eye and it finally goes to the “collector channels” and due to the less amount of aqueous humor fluid flow from the drainage angle, the pressure in the eye starts to increase. For this study, the canal of Schlemm is assumed as a permeable channel. And it is connected by trabecular meshwork. The inner layer of the canal's wall has been assumed as permeable. And the aqueous humor drains into the canal through this porous tissue wall. The objective of this paper is to discuss the effect of prostaglandin analogs on intraocular pressure as the Prostaglandin Analogs work by increasing the outflow of aqueous from the eye.

scholarly journals New Insights Into Pathophysiological Mechanisms Regulating Conventional Aqueous Humor Outflow

Medicina ◽  
2013 ◽  
Vol 49 (4) ◽  
pp. 26 ◽  
Author(s):  
Daiva Paulavičiūtė-Baikštienė ◽  
Rūta Baršauskaitė ◽  
Ingrida Janulevičienė
Keyword(s):  
Intraocular Pressure ◽  
Aqueous Humor ◽  
Trabecular Meshwork ◽  
Kinase Inhibitors ◽  
Transforming Growth Factor ◽  
Protein Kinase Inhibitors ◽  
Pathophysiological Mechanisms ◽  
Aqueous Humor Outflow ◽  
Trabecular Meshwork Cells ◽  
Glaucoma Treatment

The aim of the article was to overview the pathophysiology of the conventional outflow pathway, trabecular meshwork, and intraocular pressure and to discuss the options of future glaucoma treatment directed to improvement in aqueous outflow. The literature search in the Medline, Embase, and Cochrane databases from April to May 2012 was performed; a total of 47 articles analyzed. The diminished conventional pathway may be altered by several pathophysiological mechanisms like TM obstruction caused by transforming growth factor-β2, clastic nondeformable cells, macrophages leaking from hypermature cataract, iris pigment, lens capsular fragments after YAG-laser posterior capsulotomy, proteins and their subfragments. It is known that trabecular meshwork contraction reduces outflow, and the actomyosin system is directly linked to this mechanism. New glaucoma drugs are still under investigation, but it is already proven that agents such as latranculin-B are effective in improving aqueous drainage. Selective Rho-associated coiled coilforming protein kinase inhibitors have been shown to cause a significant improvement in outflow facility and may become a new option for glaucoma treatment. Caldesmon negatively regulates actin-myosin interactions and thus increases outflow. Stem cells may replace missing or nonfunctional trabecular meshwork cells and hopefully will bring a new treatment solution. Pathophysiological mechanisms regulating conventional aqueous humor outflow are still not fully understood and require further investigations. Future treatment decisions should be directed to a specific mechanism regulating an elevation in intraocular pressure.

scholarly journals Mechanotransduction and dynamic outflow regulation in trabecular meshwork requires Piezo1 channels

2020 ◽  
Author(s):  
Oleg Yarishkin ◽  
Tam T. T. Phuong ◽  
Jackson M. Baumann ◽  
Michael L. De Ieso ◽  
Felix Vazquez-Chona ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Shear Flow ◽  
Aqueous Humor ◽  
Trabecular Meshwork ◽  
Molecular Mechanisms ◽  
Pressure Sensors ◽  
Focal Adhesions ◽  
Ruthenium Red ◽  
Pressure Transducers ◽  
Aqueous Humor Outflow

AbstractMechanosensitivity of the trabecular meshwork (TM) is a key determinant of intraocular pressure (IOP) yet our understanding of the molecular mechanisms that subserve it remains in its infancy. Here, we show that mechanosensitive Piezo1 channels modulate the TM pressure response via calcium signaling and dynamics of the conventional outflow pathway. Pressure steps evoked fast, inactivating cation currents and calcium signals that were inhibited by Ruthenium Red, GsMTx4 and Piezo1 shRNA. Piezo1 expression was confirmed by transcript and protein analysis, and by visualizing Yoda1-mediated currents and [Ca2+]i elevations in primary human TM cells. Piezo1 activation was obligatory for transduction of physiological shear stress and was coupled to reorganization of F-actin cytoskeleton and focal adhesions. The importance of Piezo1 channels as pressure sensors was shown by the GsMTx4 -dependence of the pressure-evoked current and conventional outflow function. We also demonstrate that Piezo1 collaborates with the stretch-activated TRPV4 channel, which mediated slow, delayed currents to pressure steps. Collectively, these results suggest that TM mechanosensitivity utilizes kinetically, regulatory and functionally distinct pressure transducers to inform the cells about force-sensing contexts. Piezo1-dependent control of shear flow sensing, calcium homeostasis, cytoskeletal dynamics and pressure-dependent outflow suggests a novel potential therapeutic target for treating glaucoma.Significance StatementTrabecular meshwork (TM) is a highly mechanosensitive tissue in the eye that regulates intraocular pressure through the control of aqueous humor drainage. Its dysfunction underlies the progression of glaucoma but neither the mechanisms through which TM cells sense pressure nor their role in aqueous humor outflow are understood at the molecular level. We identified the Piezo1 channel as a key TM transducer of tensile stretch, shear flow and pressure. Its activation resulted in intracellular signals that altered organization of the cytoskeleton and cell-extracellular matrix contacts, and modulated the trabecular component of aqueous outflow whereas another channel, TRPV4, mediated a delayed mechanoresponse. These findings provide a new mechanistic framework for trabecular mechanotransduction and its role in the regulation of fast fluctuations in ocular pressure, as well as chronic remodeling of TM architecture that epitomizes glaucoma.

scholarly journals Pharmacologic Trabeculectomy—Modulation of Aqueous Humor Outflow Through the Trabecular Meshwork

2015 ◽  
Vol 8 (1) ◽  
pp. 46
Author(s):  
Syed Shoeb Ahmad ◽  
Syed Zia-ur-Rahman ◽  
Norlina Ramli ◽  
Shuaibah Abdul Ghani ◽  
◽  
...  
Keyword(s):  
Aqueous Humor ◽  
Trabecular Meshwork ◽  
Ciliary Body ◽  
Aqueous Humor Outflow ◽  
Aqueous Humor Dynamics ◽  
Aqueous Outflow

“Pharmacologic trabeculectomy” is a term used to describe the modulation of aqueous outflow by the biochemical manipulation of the trabecular meshwork. Most of the medications currently in use either reduce aqueous production or increase its outflow through the ciliary body. However, there is a new group of agents being investigated, which can increase the facility of aqueous humor outflow through the trabecular meshwork. Thus, these agents will be able to provide a more physiologic means to control aqueous humor dynamics. This review sheds light on this concept of “medical trabeculectomy.”

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