scholarly journals Complement System in Pathogenesis of AMD: Dual Player in Degeneration and Protection of Retinal Tissue

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Milosz P. Kawa ◽  
Anna Machalinska ◽  
Dorota Roginska ◽  
Boguslaw Machalinski
Keyword(s):  
Complement System ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Complement Components ◽  
Retinal Tissue ◽  
Age Related ◽  
Cellular Debris ◽  
Active Complement

Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly, especially in Western countries. Although the prevalence, risk factors, and clinical course of the disease are well described, its pathogenesis is not entirely elucidated. AMD is associated with a variety of biochemical abnormalities, including complement components deposition in the retinal pigment epithelium-Bruch’s membrane-choriocapillaris complex. Although the complement system (CS) is increasingly recognized as mediating important roles in retinal biology, its particular role in AMD pathogenesis has not been precisely defined. Unrestricted activation of the CS following injury may directly damage retinal tissue and recruit immune cells to the vicinity of active complement cascades, therefore detrimentally causing bystander damage to surrounding cells and tissues. On the other hand, recent evidence supports the notion that an active complement pathway is a necessity for the normal maintenance of the neurosensory retina. In this scenario, complement activation appears to have beneficial effect as it promotes cell survival and tissue remodeling by facilitating the rapid removal of dying cells and resulting cellular debris, thus demonstrating anti-inflammatory and neuroprotective activities. In this review, we discuss both the beneficial and detrimental roles of CS in degenerative retina, focusing on the diverse aspects of CS functions that may promote or inhibit macular disease.

Tractional Maculopathies in Age-related Macular Degeneration

2012 ◽  
Vol 05 (02) ◽  
pp. 119 ◽  
Author(s):  
Cynthia X Qian ◽  
William J Foster ◽  
Flavio A Rezende ◽  
◽  
◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
The Elderly ◽  
Developed Countries ◽  
Age Related Macular Degeneration ◽  
The Past ◽  
Age Related ◽  
Surgical Options ◽  
Made In

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. Much progress has been and continues to be made in search of better visual outcomes for dry and exudative AMD. Over the past decade, the importance of vitreomacular attachments has been recognized in AMD. In this article, we better characterize and describe vitreomacular and photoreceptor-retinal pigment epithelium interface relationships in AMD among treated and untreated patients and describe the surgical options available as well as their outcomes and possible complications.

scholarly journals Age-related Macular Degeneration: Current Knowledge of Zinc Metalloproteinases Involvement

2019 ◽  
Vol 20 (9) ◽  
pp. 903-918 ◽  
Author(s):  
Francesca Liva ◽  
Doretta Cuffaro ◽  
Elisa Nuti ◽  
Susanna Nencetti ◽  
Elisabetta Orlandini ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Current Knowledge ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Critical Role ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Tissue Inhibitors Of Metalloproteinase ◽  
Age Related ◽  
A Disintegrin And Metalloproteinase

Background: Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly with limited therapeutic options. The disease is characterized by photoreceptor loss in the macula and reduced Retinal Pigment Epithelium (RPE) function, associated with matrix degradation, cell proliferation, neovascularization and inflammation. Matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) play a critical role in the physiology of extracellular matrix (ECM) turnover and, in turn, in ECM pathologies, such as AMD. A balance between the activities of MMPs and Tissue Inhibitors of Metalloproteinase (TIMPs) is crucial for the integrity of the ECM components; indeed, a dysregulation in the ratio of these factors produces profound changes in the ECM, including thickening and deposit formation, which eventually might lead to AMD development. Objective: This article reviews the relevance and impact of zinc metalloproteinases on the development of AMD and their roles as biomarkers and/or therapeutic targets. We illustrate some studies on several inhibitors of MMPs currently used to dissect physiological properties of MMPs. Moreover, all molecules or technologies used to control MMP and ADAM activity in AMD are analyzed. Conclusion: This study underlines the changes in the activity of MMPs expressed by RPE cells, highlights the functions of already used MMP inhibitors and consequently suggests their application as therapeutic agents for the treatment of AMD.

scholarly journals Cell Therapy for Retinal Dystrophies: From Cell Suspension Formulation to Complex Retinal Tissue Bioengineering

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Karim Ben M’Barek ◽  
Christelle Monville
Keyword(s):  
Cell Therapy ◽  
Current Knowledge ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Future Research ◽  
Therapeutic Effects ◽  
Primary Defect ◽  
Retinal Tissue ◽  
Age Related

Retinal degeneration is an irreversible phenomenon caused by various disease conditions including age-related macular degeneration (AMD) and retinitis pigmentosa (RP). During the course of these diseases, photoreceptors (PRs) are susceptible to degeneration due to their malfunctions or to a primary dysfunction of the retinal pigment epithelium (RPE). Once lost, these cells could not be endogenously regenerated in humans, and cell therapy to replace the lost cells is one of the promising strategies to recover vision. Depending on the nature of the primary defect and the stage of the disease, RPE cells, PRs, or both might be transplanted to achieve therapeutic effects. We describe in this review the current knowledge and recent progress to develop such approaches. The different cell sources proposed for cell therapy including human pluripotent stem cells are presented with their advantages and limits. Another critical aspect described herein is the pharmaceutical formulation of the end product to be delivered into the eye of patients. Finally, we also outline the future research directions in order to develop a complex multilayered retinal tissue for end-stage patients.

scholarly journals Complement System and Potential Therapeutics in Age-Related Macular Degeneration

2021 ◽  
Vol 22 (13) ◽  
pp. 6851
Author(s):  
Young-Gun Park ◽  
Yong-Soo Park ◽  
In-Beom Kim
Keyword(s):  
Macular Degeneration ◽  
Complement System ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelium Cell ◽  
Immune Surveillance ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
The Complement System

Age-related macular degeneration (AMD) is a complex multifactorial disease characterized in its late form by neovascularization (wet type) or geographic atrophy of the retinal pigment epithelium cell layer (dry type). The complement system is an intrinsic component of innate immunity. There has been growing evidence that the complement system plays an integral role in maintaining immune surveillance and homeostasis in AMD. Based on the association between the genotypes of complement variants and AMD occurrence and the presence of complement in drusen from AMD patients, the complement system has become a therapeutic target for AMD. However, the mechanism of complement disease propagation in AMD has not been fully understood. This concise review focuses on an overall understanding of the role of the complement system in AMD and its ongoing clinical trials. It provides further insights into a strategy for the treatment of AMD targeting the complement system.

scholarly journals NLRP3 Inflammasome: Activation and Regulation in Age-Related Macular Degeneration

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Jiangyuan Gao ◽  
Ruozhou Tom Liu ◽  
Sijia Cao ◽  
Jing Z. Cui ◽  
Aikun Wang ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
The Elderly ◽  
Geographic Atrophy ◽  
Age Related Macular Degeneration ◽  
Inflammasome Activation ◽  
Related Factors ◽  
Rpe Cells ◽  
Age Related

Age-related macular degeneration (AMD) is the leading cause of legal blindness in the elderly in industrialized countries. AMD is a multifactorial disease influenced by both genetic and environmental risk factors. Progression of AMD is characterized by an increase in the number and size of drusen, extracellular deposits, which accumulate between the retinal pigment epithelium (RPE) and Bruch’s membrane (BM) in outer retina. The major pathways associated with its pathogenesis include oxidative stress and inflammation in the early stages of AMD. Little is known about the interactions among these mechanisms that drive the transition from early to late stages of AMD, such as geographic atrophy (GA) or choroidal neovascularization (CNV). As part of the innate immune system, inflammasome activation has been identified in RPE cells and proposed to be a causal factor for RPE dysfunction and degeneration. Here, we will first review the classic model of inflammasome activation, then discuss the potentials of AMD-related factors to activate the inflammasome in both nonocular immune cells and RPE cells, and finally introduce several novel mechanisms for regulating the inflammasome activity.

scholarly journals Oxidative Stress, Hypoxia, and Autophagy in the Neovascular Processes of Age-Related Macular Degeneration

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Janusz Blasiak ◽  
Goran Petrovski ◽  
Zoltán Veréb ◽  
Andrea Facskó ◽  
Kai Kaarniranta
Keyword(s):  
Oxidative Stress ◽  
Macular Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
The Elderly ◽  
Developed Countries ◽  
The Body ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
The Rich

Age-related macular degeneration (AMD) is the leading cause of severe and irreversible loss of vision in the elderly in developed countries. AMD is a complex chronic neurodegenerative disease associated with many environmental, lifestyle, and genetic factors. Oxidative stress and the production of reactive oxygen species (ROS) seem to play a pivotal role in AMD pathogenesis. It is known that the macula receives the highest blood flow of any tissue in the body when related to size, and anything that can reduce the rich blood supply can cause hypoxia, malfunction, or disease. Oxidative stress can affect both the lipid rich retinal outer segment structure and the light processing in the macula. The response to oxidative stress involves several cellular defense reactions, for example, increases in antioxidant production and proteolysis of damaged proteins. The imbalance between production of damaged cellular components and degradation leads to the accumulation of detrimental products, for example, intracellular lipofuscin and extracellular drusen. Autophagy is a central lysosomal clearance system that may play an important role in AMD development. There are many anatomical changes in retinal pigment epithelium (RPE), Bruch’s membrane, and choriocapillaris in response to chronic oxidative stress, hypoxia, and disturbed autophagy and these are estimated to be crucial components in the pathology of neovascular processes in AMD.

scholarly journals Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Keng Siang Lee ◽  
Shuxiao Lin ◽  
David A. Copland ◽  
Andrew D. Dick ◽  
Jian Liu
Keyword(s):  
Retinal Pigment Epithelium ◽  
Macular Degeneration ◽  
Cellular Senescence ◽  
Vision Loss ◽  
Inflammatory Responses ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Age Related

AbstractAge-related macular degeneration (AMD), a degenerative disease in the central macula area of the neuroretina and the supporting retinal pigment epithelium, is the most common cause of vision loss in the elderly. Although advances have been made, treatment to prevent the progressive degeneration is lacking. Besides the association of innate immune pathway genes with AMD susceptibility, environmental stress- and cellular senescence-induced alterations in pathways such as metabolic functions and inflammatory responses are also implicated in the pathophysiology of AMD. Cellular senescence is an adaptive cell process in response to noxious stimuli in both mitotic and postmitotic cells, activated by tumor suppressor proteins and prosecuted via an inflammatory secretome. In addition to physiological roles in embryogenesis and tissue regeneration, cellular senescence is augmented with age and contributes to a variety of age-related chronic conditions. Accumulation of senescent cells accompanied by an impairment in the immune-mediated elimination mechanisms results in increased frequency of senescent cells, termed “chronic” senescence. Age-associated senescent cells exhibit abnormal metabolism, increased generation of reactive oxygen species, and a heightened senescence-associated secretory phenotype that nurture a proinflammatory milieu detrimental to neighboring cells. Senescent changes in various retinal and choroidal tissue cells including the retinal pigment epithelium, microglia, neurons, and endothelial cells, contemporaneous with systemic immune aging in both innate and adaptive cells, have emerged as important contributors to the onset and development of AMD. The repertoire of senotherapeutic strategies such as senolytics, senomorphics, cell cycle regulation, and restoring cell homeostasis targeted both at tissue and systemic levels is expanding with the potential to treat a spectrum of age-related diseases, including AMD.

scholarly journals CFH Loss in Human RPE Cells Leads to Inflammation and Complement System Dysregulation via the NF-κB Pathway

2021 ◽  
Vol 22 (16) ◽  
pp. 8727
Author(s):  
Angela Armento ◽  
Tiziana L. Schmidt ◽  
Inga Sonntag ◽  
David A. Merle ◽  
Mohamed Ali Jarboui ◽  
...  
Keyword(s):  
Complement System ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Major Pathway ◽  
Rpe Cells ◽  
Age Related

Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease, and chronic inflammatory processes may be involved. Besides aging and lifestyle factors as drivers of AMD, a strong genetic association to AMD is found in genes of the complement system, with a single polymorphism in the complement factor H gene (CFH), accounting for the majority of AMD risk. However, the exact mechanism of CFH dysregulation confers such a great risk for AMD and its role in RPE cell homeostasis is unclear. To explore the role of endogenous CFH locally in RPE cells, we silenced CFH in human hTERT-RPE1 cells. We demonstrate that endogenously expressed CFH in RPE cells modulates inflammatory cytokine production and complement regulation, independent of external complement sources, or stressors. We show that loss of the factor H protein (FH) results in increased levels of inflammatory mediators (e.g., IL-6, IL-8, GM-CSF) and altered levels of complement proteins (e.g., C3, CFB upregulation, and C5 downregulation) that are known to play a role in AMD. Moreover, our results identify the NF-κB pathway as the major pathway involved in regulating these inflammatory and complement factors. Our findings suggest that in RPE cells, FH and the NF-κB pathway work in synergy to maintain inflammatory and complement balance, and in case either one of them is dysregulated, the RPE microenvironment changes towards a proinflammatory AMD-like phenotype.

Tissue engineering of retina and Bruch’s membrane: a review of cells, materials and processes

2018 ◽  
Vol 102 (9) ◽  
pp. 1182-1187 ◽  
Author(s):  
Yong Sheng Edgar Tan ◽  
Pu Jiang Shi ◽  
Chang-J Choo ◽  
Augustinus Laude ◽  
Wai Yee Yeong
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Cell Sheet ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Preclinical Model ◽  
Bruch's Membrane ◽  
Bruch’S Membrane ◽  
Cell Sheet Engineering ◽  
Age Related

The biological, structural and functional configuration of Bruch’s membrane (BM) is significantly relevant to age-related macular degeneration (AMD) and other chorioretinal diseases, and AMD is one of the leading causes of blindness in the elderly worldwide. The configuration may worsen along with the ageing of retinal pigment epithelium and BM that finally leads to AMD. Thus, the scaffold-based tissue-engineered retina provides an innovative alternative for retinal tissue repair. The cell and material requirements for retinal repair are discussed including cell sheet engineering, decellularised membrane and tissue-engineered membranes. Further, the challenges and potential in realising a whole tissue model construct for retinal regeneration are highlighted herein. This review article provides a framework for future development of tissue-engineered retina as a preclinical model and possible treatments for AMD.

scholarly journals CFH loss in human RPE cells leads to inflammation and complement system dysregulation via the NF-ƙB pathway

2021 ◽  
Author(s):  
Angela Armento ◽  
Tiziana Luisa Schmidt ◽  
Inga Sonntag ◽  
David Merle ◽  
Mohamed-ali Jarboui ◽  
...  
Keyword(s):  
Complement System ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Factor ◽  
Major Pathway ◽  
Rpe Cells ◽  
Age Related

Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease and chronic inflammatory processes may be involved. Besides ageing and lifestyle factors as drivers of AMD, a strong genetic association to AMD is found in genes of the complement system, with a single polymorphism in the complement factor H gene (CFH), accounting for the majority of AMD risk. However, the exact mechanism by which CFH dysregulation confers such a great risk for AMD and its role in RPE cells homeostasis is unclear. To explore the role of endogenous CFH locally in RPE cells, we silenced CFH in human hTERT-RPE1 cells. We demonstrate that endogenously expressed CFH in RPE cells modulates inflammatory cytokine production and complement regulation, independent of external complement sources or stressors. We show that loss of the factor H protein (FH) results in increased levels of inflammatory mediators (e.g. IL-6, IL-8, GM-CSF) and altered levels of complement proteins (e.g. C3, CFB upregulation and C5 downregulation) that are known to play a role in AMD. Moreover, we identified the NF-ƙB pathway as the major pathway involved in the regulation of these inflammatory and complement factors. Our findings suggest that in RPE cells, FH and the NF-ƙB pathway work in synergy to maintain inflammatory and complement balance and in case either one of them is dysregulated, the RPE microenvironment changes towards a pro-inflammatory AMD-like phenotype.

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