scholarly journals Caveolin-1 Promotes Cellular Senescence in Exchange for Blocking Subretinal Fibrosis in Age-Related Macular Degeneration

2020 ◽  
Vol 61 (11) ◽  
pp. 21
Author(s):  
Hideyuki Shimizu ◽  
Kazuhisa Yamada ◽  
Ayana Suzumura ◽  
Keiko Kataoka ◽  
Kei Takayama ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Cellular Senescence ◽  
Age Related Macular Degeneration ◽  
Caveolin 1 ◽  
Age Related ◽  
Subretinal Fibrosis

scholarly journals Macrophage to myofibroblast transition contributes to subretinal fibrosis secondary to neovascular age-related macular degeneration

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Karis Little ◽  
Maria Llorián-Salvador ◽  
Miao Tang ◽  
Xuan Du ◽  
Stephen Marry ◽  
...  
Keyword(s):  
Growth Factor ◽  
Macular Degeneration ◽  
Transforming Growth Factor ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Two Stage ◽  
Blocking Antibody ◽  
Age Related ◽  
Subretinal Fibrosis ◽  
Isolectin B4

Abstract Background Macular fibrosis causes irreparable vision loss in neovascular age-related macular degeneration (nAMD) even with anti-vascular endothelial growth factor (VEGF) therapy. Inflammation is known to play an important role in macular fibrosis although the underlying mechanism remains poorly defined. The aim of this study was to understand how infiltrating macrophages and complement proteins may contribute to macular fibrosis. Methods Subretinal fibrosis was induced in C57BL/6J mice using the two-stage laser protocol developed by our group. The eyes were collected at 10, 20, 30 and 40 days after the second laser and processed for immunohistochemistry for infiltrating macrophages (F4/80 and Iba-1), complement components (C3a and C3aR) and fibrovascular lesions (collagen-1, Isolectin B4 and α-SMA). Human retinal sections with macular fibrosis were also used in the study. Bone marrow-derived macrophages (BMDMs) from C57BL/6J mice were treated with recombinant C3a, C5a or TGF-β for 48 and 96 h. qPCR, Western blot and immunohistochemistry were used to examine the expression of myofibroblast markers. The involvement of C3a-C3aR pathway in macrophage to myofibroblast transition (MMT) and subretinal fibrosis was further investigated using a C3aR antagonist (C3aRA) and a C3a blocking antibody in vitro and in vivo. Results Approximately 20~30% of F4/80+ (or Iba-1+) infiltrating macrophages co-expressed α-SMA in subretinal fibrotic lesions both in human nAMD eyes and in the mouse model. TGF-β and C3a, but not C5a treatment, significantly upregulated expression of α-SMA, fibronectin and collagen-1 in BMDMs. C3a-induced upregulation of α-SMA, fibronectin and collagen-1 in BMDMs was prevented by C3aRA treatment. In the two-stage laser model of induced subretinal fibrosis, treatment with C3a blocking antibody but not C3aRA significantly reduced vascular leakage and Isolectin B4+ lesions. The treatment did not significantly alter collagen-1+ fibrotic lesions. Conclusions MMT plays a role in macular fibrosis secondary to nAMD. MMT can be induced by TGF-β and C3a but not C5a. Further research is required to fully understand the role of MMT in macular fibrosis. Graphical abstract Macrophage to myofibroblast transition (MMT) contributes to subretinal fibrosis. Subretinal fibrosis lesions contain various cell types, including macrophages and myofibroblasts, and are fibrovascular. Myofibroblasts are key cells driving pathogenic fibrosis, and they do so by producing excessive amount of extracellular matrix proteins. We have found that infiltrating macrophages can transdifferentiate into myofibroblasts, a phenomenon termed macrophage to myofibroblast transition (MMT) in macular fibrosis. In addition to TGF-β1, C3a generated during complement activation in CNV can also induce MMT contributing to macular fibrosis. RPE = retinal pigment epithelium. BM = Bruch’s membrane. MMT = macrophage to myofibroblast transition. TGFB = transforming growth factor β. a-SMA = alpha smooth muscle actin. C3a = complement C3a.

PREVALENCE AND RISK FACTORS FOR THE DEVELOPMENT OF PHYSICIAN-GRADED SUBRETINAL FIBROSIS IN EYES TREATED FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION

Retina ◽  
2020 ◽  
Vol 40 (12) ◽  
pp. 2285-2295 ◽  
Author(s):  
Kelvin Yi Chong Teo ◽  
Aaron W. Joe ◽  
Vuong Nguyen ◽  
Alessandro Invernizzi ◽  
Jennifer J. Arnold ◽  
...  
Keyword(s):  
Risk Factors ◽  
Macular Degeneration ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Subretinal Fibrosis

scholarly journals Cellular Senescence in Age-Related Macular Degeneration: Can Autophagy and DNA Damage Response Play a Role?

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Janusz Blasiak ◽  
Malgorzata Piechota ◽  
Elzbieta Pawlowska ◽  
Magdalena Szatkowska ◽  
Ewa Sikora ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Macular Degeneration ◽  
Dna Damage Response ◽  
Cellular Senescence ◽  
Cell Senescence ◽  
Age Related Macular Degeneration ◽  
Rpe Cells ◽  
Age Related ◽  
Damage Response

Age-related macular degeneration (AMD) is the main reason of blindness in developed countries. Aging is the main AMD risk factor. Oxidative stress, inflammation and some genetic factors play a role in AMD pathogenesis. AMD is associated with the degradation of retinal pigment epithelium (RPE) cells, photoreceptors, and choriocapillaris. Lost RPE cells in the central retina can be replaced by their peripheral counterparts. However, if they are senescent, degenerated regions in the macula cannot be regenerated. Oxidative stress, a main factor of AMD pathogenesis, can induce DNA damage response (DDR), autophagy, and cell senescence. Moreover, cell senescence is involved in the pathogenesis of many age-related diseases. Cell senescence is the state of permanent cellular division arrest and concerns only mitotic cells. RPE cells, although quiescent in the retina, can proliferate in vitro. They can also undergo oxidative stress-induced senescence. Therefore, cellular senescence can be considered as an important molecular pathway of AMD pathology, resulting in an inability of the macula to regenerate after degeneration of RPE cells caused by a factor inducing DDR and autophagy. It is too early to speculate about the role of the mutual interplay between cell senescence, autophagy, and DDR, but this subject is worth further studies.

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 Fenofibrate Inhibits Subretinal Fibrosis Through Suppressing TGF‐β—Smad2/3 signaling and Wnt signaling in Neovascular Age‐Related Macular Degeneration

2020 ◽  
Vol 11 ◽  
Author(s):  
Qian Chen ◽  
Nan Jiang ◽  
Yuhan Zhang ◽  
Sihao Ye ◽  
Xu Liang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Wnt Signaling ◽  
Macular Degeneration ◽  
Müller Cells ◽  
Tissue Growth ◽  
Age Related Macular Degeneration ◽  
Collagen Deposition ◽  
Muller Cells ◽  
Age Related ◽  
Subretinal Fibrosis

Subretinal fibrosis is a common pathological change that causes vision loss in neovascular age-related macular degeneration (nAMD). Treatment modalities for subretinal fibrosis are limited. In the present study, the effects of fenofibrate, a specific peroxisome proliferator–activated receptor alpha agonist, on subretinal fibrosis of nAMD were tested, and its molecular mechanisms of action were delineated. Collagen deposition and protein expression of fibrotic markers, such as vimentin, collagen-1, alpha-smooth muscle actin, and fibronectin, were increased in very low–density lipoprotein receptor (VLDLR) knockout mouse, indicating Vldlr−/− mice can be used as a model for subretinal fibrosis. Fenofibrate suppressed subretinal fibrosis of Vldlr−/− mice by reducing collagen deposition and protein expression of fibrotic markers. Two fibrotic pathways, TGF-β—Smad2/3 signaling and Wnt signaling, were significantly up-regulated, while inhibited by fenofibrate in Vldlr−/− retinas. Moreover, fenofibrate significantly reduced the downstream connective tissue growth factor (CTGF) expression of these two pathways. Müller cells were a major source of CTGF in Vldlr−/− retinas. Fenofibrate was capable of suppressing Müller cell activation and thus reducing the release of CTGF in Vldlr−/− retinas. In cultured Müller cells, fenofibrate reversed TGF-β2–induced up-regulation of Wnt signaling and CTGF expression. These findings suggested that fenofibrate inhibits subretinal fibrosis by suppressing TGF-β—Smad2/3 signaling and Wnt signaling and reducing CTGF expression, and thus, fenofibrate could be a potential treatment for nAMD with subretinal fibrosis.

scholarly journals Autotranslocation of the pigment epithelium-choroid complex in treatment of age-related macular degeneration scarring stage

2021 ◽  
Vol 13 (3) ◽  
pp. 97-104
Author(s):  
Sergei V. Sosnovskii ◽  
Ernest V. Boiko ◽  
Dzhambulat Kh. Oskanov
Keyword(s):  
Macular Degeneration ◽  
Pigment Epithelium ◽  
Antiangiogenic Therapy ◽  
Angiogenesis Inhibitors ◽  
Original Method ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Subretinal Fibrosis ◽  
Subretinal Surgery

The gold standard of the neovascular age-related macular degeneration treatment is the intravitreal administration of angiogenesis inhibitors. In subretinal macular fibrosis, antiangiogenic therapy is not effective. In such cases, subretinal surgery is used, in particular, autotranslocation of pigment epithelium-choroid complex. This paper presents a case of successful use of this method in a 77 y.o. female patient with subretinal fibrosis in the macular area as an outcome of neovascular age-related macular degeneration. An original method of translocation of pedicled pigment epithelium-choroid complex from the paramacular area to the macula was used. In 24 months, the visual acuity increased from 0.01 to 0.07; the central fixation was restored; the absolute positive central scotoma disappeared. During all the post-operative follow-up period, the full-rate pigment epithelium-choroid perfusion in the choroid of the translocated flap, the loss of choroidal neovascularization activity signs and of indications for intravitreal administration of angiogenesis inhibitors were proved.

scholarly journals Baseline predictors for subretinal fibrosis in neovascular age-related macular degeneration

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Philipp K. Roberts ◽  
Markus Schranz ◽  
Alice Motschi ◽  
Sylvia Desissaire ◽  
Valentin Hacker ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Subretinal Fluid ◽  
Retinal Hemorrhage ◽  
Age Related Macular Degeneration ◽  
Fundus Photography ◽  
Age Related ◽  
Increased Risk ◽  
Significant Difference ◽  
Subretinal Fibrosis ◽  
Treatment Naïve

AbstractTo find baseline predictors for subretinal fibrosis (SF) in neovascular age-related macular degeneration (nAMD). Forty-five eyes of 45 participants with treatment-naïve nAMD were consecutively enrolled and treated according to a standardized treat-and-extend protocol. Spectral-domain optical coherence tomography (OCT), color fundus photography and fluorescein angiography as well as novel imaging modalities polarization-sensitive OCT and OCT angiography (OCTA) were performed to detect SF after 1 year and find baseline predictors for SF development. Baseline OCTA scans were evaluated for quantitative features such as lesion area, vessel area, vessel junctions, vessel length, vessel endpoints and mean lacunarity. Additionally, the type of macular neovascularization, the presence of subretinal fluid, intraretinal fluid (IRF), subretinal hyperreflective material (SHRM), retinal hemorrhage as well as best-corrected visual acuity (BCVA) were evaluated. After 12 months 8 eyes (18%) developed SF. Eyes with SF had worse baseline BCVA (p = .001) and a higher prevalence of IRF (p = .014) and SHRM at baseline (p = .017). There was no significant difference in any of the evaluated quantitative OCTA parameters (p > .05) between eyes with and without SF. There were no quantitative baseline microvascular predictors for SF in our study. Low baseline BCVA, the presence of IRF and SHRM, however, are easily identifiable baseline parameters indicating increased risk.

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