Topical Prostaglandin F2α Treatment Reduces Collagen Types I, III, and IV in the Monkey Uveoscleral Outflow Pathway

Sagara, Takeshi; Gaton, Dan D.; Lindsey, James D.; Gabelt, B’Ann T.; Kaufman, Paul L.; Weinreb, Robert N.

doi:10.1001/archopht.117.6.794

Cited by 161 publications

(96 citation statements)

References 28 publications

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“…Their earlier work had shown that following treatment of human ciliary muscle cells in culture with PGF 2α , collagens type I and III were reduced while matrix metalloproteinases 1, 2, 3 and 9 were increased (Lindsey et al, 1996;Lindsey et al, 1997). In vivo, following topical treatment of monkey eyes for 5 days with PGF 2α , collagen types I, III, and IV immunoreactivity in the ciliary muscle and adjacent sclera was reduced (Sagara et al, 1999) while matrix metalloproteinases 1, 2, and 3 were increased (Table 1) (Gaton et al, 2001;Weinreb et al, 2002). Thus the reduction of ciliary muscle extracellular matrix within the interbundle spaces reduces hydraulic resistance to aqueous movement and contributes to the PG-mediated increase of uveoscleral outflow.…”

Section: Prostaglandins and Enhancement Of Uveoscleral Outflowmentioning

confidence: 99%

Enhancing trabecular outflow by disrupting the actin cytoskeleton, increasing uveoscleral outflow with prostaglandins, and understanding the pathophysiology of presbyopia

Kaufman

2008

Experimental Eye Research

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Several major areas of work by the author and his international collaborators are reviewed. 1) The ciliary muscle in the nonhuman primate eye was disinserted at the scleral spur. Pilocarpine was then ineffective in increasing outflow facility, indicating that ciliary muscle contraction mediated the IOPlowering effect of muscarinic cholinergics. 2) Compounds such as cytochalasins, H-7 and latrunculin A/B, which alter the actin cytoskeleton, cellular contractility and cellular adhesions in cultured trabecular meshwork cells, relaxed trabecular pathway cells and consequently the meshwork itself so as to decrease IOP and enhance trabecular outflow facility in nonhuman primates. Gene transfer approaches utilizing C3 and caldesmon over-expression by viral vectors to target specific steps in the cellular contractility/cytoskeleton/cell adhesion cascades characteristically altered trabecular meshwork cell morphology and increased outflow facility in organ-cultured anterior segments. 3) Prostaglandin F 2α analogues enhanced matrix metalloproteinase production by ciliary muscle cells and scleral fibroblasts, leading to remodeling of the extracellular matrix of the ciliary muscle and sclera and consequently to increased uveoslceral outflow and decreased IOP in primates. 4) The rhesus monkey was an excellent model for human presbyopia, losing the accommodative response to cholinergic stimulation in the same timeframe relative to lifespan. No changes were found in ciliary muscle enzymes involved in acetylcholine biosynthesis or degradation or in muscarinic receptor numbers or affinity. Contractility of isolated ciliary muscle did not diminish with age, but posterior ciliary muscle attachments stiffened, suggesting a possible role in restricting muscle and consequently lens movement during accommodation. A model to reproducibly stimulate accommodation through central stimulation of the Edinger-Westphal nucleus was developed. Goniovideography and ultrasound biomicroscopic techniques allowed real-time recording and analysis of the accommodation-relevant structures. Surgical ablation of the intraocular structures involved in the accommodation response has led to further understanding of their roles and changes with age related to presbyopia. 5) Global collaborations such as those involved in these studies will be essential in the future, as science becomes "bigger".Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The story I will tell is embodied in the title. It is about recognizing questions, asking how and why things happen, recognizing signs along the way, and about focus yet w...

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Section: Prostaglandins and Enhancement Of Uveoscleral Outflowmentioning

confidence: 99%

Enhancing trabecular outflow by disrupting the actin cytoskeleton, increasing uveoscleral outflow with prostaglandins, and understanding the pathophysiology of presbyopia

Kaufman

2008

Experimental Eye Research

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“…FP-agonists lead to a loss of connective tissue within the ciliary body and increase the expression and/or secretion of MMPs. 8,13,15,33 However, studies have not provided direct evidence that MMPs are involved in the ocular hypotensive response to FP-agonists.…”

Section: Discussionmentioning

confidence: 99%

“…14 Further, a reduction in these collagens was observed in the ciliary muscle of inflamed monkey eyes previously treated with PGF 2␣ -IE, in which uveoscleral outflow was also increased. 8,34 Thus, increased degradation of ciliary muscle ECM by MMP is thought to decrease the hydraulic resistance to uveoscleral outflow, thereby lowering the IOP in the eye. To provide direct evidence that the secretion and activation of MMPs was involved in the IOP responses to latanoprost, rats were pretreated with the broad-spectrum MMP inhibitor, GM-6001.…”

Section: Discussionmentioning

confidence: 99%

“…Topical treatment with prostaglandin F 2␣ analogs alters the extracellular matrix (ECM) in the tissues of the uveoscleral outflow pathway 8 and increases the production of matrix metalloproteinases (MMPs) in the ciliary muscle cells. [8][9][10][11][12][13][14][15] Although studies have shown that MMPs can alter conventional outflow facility in human and animal perfused eyes, 16,17 direct evidence that MMPs participate in the FPagonist-induced modulation of IOP remains to be determined.…”

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confidence: 99%

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Latanoprost-Induced Changes in Rat Intraocular Pressure: Direct or Indirect?

Husain

Yates

Crosson

2008

Journal of Ocular Pharmacology and Therapeutics

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Introduction: The topical application of prostaglandin F 2␣ (FP)-receptor agonists has been shown to significantly lower intraocular pressure (IOP) in humans and is now considered the first-line treatment for ocular hypertension. Despite the prominent role FP-receptor agonists play in the treatment of glaucoma, our understanding of how these agents lower IOP remains incomplete. The present study was designed to evaluate the role of matrix metalloproteinase (MMP) activation and the cytokine, tumor necrosis factor alpha (TNF-␣), in latanoprost-induced changes in IOP. Methods: Changes in IOP following an acute topical administration of latanoprost (60 ng) in normotensive Brown Norway rats were evaluated by means of a commercially available rebound tonometer. To examine the role of MMPs and TNF-␣ in this response, the rats were pretreated with a broad-spectrum MMP inhibitor, GM-6001 (100 g), or the TNF-␣ inhibitor, thalidomide (25 g). Results: The topical administration of latanoprost (60 ng) alone produced a biphasic change in ipsilateral IOP: an initial hypertension (4.21 Ϯ 0.52), followed by a prolonged hypotension (Ϫ4.79 Ϯ 0.65). In rats, pretreatment with GM-6001 blocked the latanoprost-induced reduction in IOP but did not prevent the initial rise in IOP. Pretreatment with thalidomide also blocked the ocular hypotension induced by latanoprost; however, thalidomide pretreatment enhanced the duration of the initial hypertension. Conclusions: These results provide evidence that the secretion and activation of MMPs and the release of TNF-␣ play a central role in the ocular hypotension induced by FP-agonists. The administration of FP-agonists appears to lower IOP directly by inducing the activation of MMPs within the ciliary body, leading to improved uveoscleral outflow and indirectly through the release of TNF-␣ within the ciliary body. Secreted TNF-␣ may then activate TNF-receptors in the uvea and trabecular meshwork, increasing both uveoscleral and conventional outflow.

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“…Extensive studies have demonstrated prostaglandin-related decreases in TM cell contractility and outflow resistance of organ-cultured anterior segments [121][122][123]. The overall mechanisms through which prostaglandins enhance AH outflow remain to be fully elucidated; however, it is widely accepted that remodeling of the ECM plays a part [124][125][126][127], and it is of note that upregulation in MMP expression, through activation of prostaglandin receptors, may be involved [89,128]. However, the unique receptor profile for each analog may induce ECM modulation via different cascade pathways.…”

Section: Traditional Topical Medications In the Management Of Glaucomamentioning

confidence: 99%

Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

O’Callaghan

Cassidy

Humphries

2017

Expert Opinion on Therapeutic Targets

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Introduction:Ocular hypertension in open-angle glaucoma is caused by a reduced rate of removal of aqueous humour (AH) from the eye, with the majority of AH draining from the anterior chamber through the conventional outflow pathway, comprising the trabecular meshwork (TM) and Schlemm's Canal. Resistance to outflow is generated, in part, by the extracellular matrix (ECM) of the outflow tissues. Current pressure-lowering topical medications largely suppress AH production, or enhance its clearance through the unconventional pathway. However, therapies targeting the ECM of the conventional pathway in order to decrease intraocular pressure have become a recent focus of attention. Areas covered: We discuss the role of ECM of the TM in outflow homeostasis and its relevance as a target for glaucoma therapy, including progress in development of topical eye formulations, together with gene therapy approaches based on inducible, virally-mediated expression of matrix metalloproteinases to enhance aqueous outflow. Expert opinion: There remains a need for improved glaucoma medications that more specifically act upon sites causative to glaucoma pathogenesis. Emerging strategies targeting the ECM of the conventional outflow pathway, or associated components of the cytoskeleton of TM cells, involving new pharmacological formulations or genetically-based therapies, are promising avenues of future glaucoma treatment. ARTICLE HISTORY

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Topical Prostaglandin F2α Treatment Reduces Collagen Types I, III, and IV in the Monkey Uveoscleral Outflow Pathway

Cited by 161 publications

References 28 publications

Enhancing trabecular outflow by disrupting the actin cytoskeleton, increasing uveoscleral outflow with prostaglandins, and understanding the pathophysiology of presbyopia

Enhancing trabecular outflow by disrupting the actin cytoskeleton, increasing uveoscleral outflow with prostaglandins, and understanding the pathophysiology of presbyopia

Latanoprost-Induced Changes in Rat Intraocular Pressure: Direct or Indirect?

Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

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