Transforming Growth Factor-Beta Inhibition Reduces Progression of Early Choroidal Neovascularization Lesions in Rats: P17 and P144 Peptides

Zarranz‐Ventura, Javier; Fernández-Robredo, Patricia; Recalde, Sergio; Salinas-Alamán, Angel; Borrás‐Cuesta, Francisco; Dotor, Javier; García‐Layana, Alfredo

doi:10.1371/journal.pone.0065434

Cited by 33 publications

(28 citation statements)

References 37 publications

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“…However, injection of anti-TGF-β and anti-TGF-βRI antibodies inhibits chronic synovial inflammation in rats with SCW-induced arthritis [38] and in CAIA mice [25]. In CIA, treatment with p17 TGF-β antagonist at the same doses shown previously to block activity of TGF-β in vivo [31,[39][40][41][42][43] did not prevent or modify the severity of the disease, neither during the induction phase nor during established arthritis. As Marinova-Mutafchieva et al have shown that TGF-β expression is induced in the joints at the time of arthritis onset, the time of treatment of CIA mice during clinical progression of disease is justified.…”

Section: Discussionmentioning

confidence: 86%

Transforming growth factor (TGF)-β signalling is increased in rheumatoid synovium but TGF-β blockade does not modify experimental arthritis

Gonzalo-Gil

Criado

Santiago

et al. 2013

Clinical and Experimental Immunology

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SummaryThe aim of this study was to analyse the distribution of regulatory and inhibitory mothers against decapentaplegic homologue (Smad) proteins as markers of active transforming growth factor (TGF)-β signalling in rheumatoid arthritis (RA) synovial tissue and to investigate the effect of TGF-β blockade in the development and progression of collagen-induced arthritis. The expression of Smad proteins in synovial tissues from RA, osteoarthritic and healthy controls was analysed by immunohistochemistry. Arthritis was induced in DBA/1 mice by immunization with chicken type-II collagen (CII). TGF-β was blocked in vivo with the specific peptide p17 starting at the time of immunization or on the day of arthritis onset. T cell population frequencies and specific responses to CII were analysed. The expression of cytokines and transcription factors was quantified in spleen and joint samples. Statistical differences between groups were compared using the Mann-Whitney U-test or one-way analysis of variance (anova) using the Kruskal-Wallis test. p-Smad-2/3 and inhibitory Smad-7 expression were detected in RA and control tissues. In RA, most lymphoid infiltrating cells showed nuclear p-Smad-2/3 without Smad-7 expression. Treatment with TGF-β antagonist did not affect clinical severity, joint inflammation and cartilage damage in collagen-induced arthritis. Frequency of T cell subsets, mRNA levels of cytokines and transcription factors, specific proliferation to CII, serum interleukin (IL)-6 and anti-CII antibodies were comparable in p17 and phosphate-buffered saline (PBS)-treated groups. The pattern of Smad proteins expression demonstrates active TGF-β signalling in RA synovium. However, specific TGF-β blockade does not have a significant effect in the mice model of collagen-induced arthritis.

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Section: Discussionmentioning

confidence: 86%

Transforming growth factor (TGF)-β signalling is increased in rheumatoid synovium but TGF-β blockade does not modify experimental arthritis

Gonzalo-Gil

Criado

Santiago

et al. 2013

Clinical and Experimental Immunology

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“…Nagineni et al [30] demonstrated that TGF-β can induce the secretion of VEGF from the retinal pigment epithelium (RPE) and choroidal cells, and play an important role in CNV in AMD. Two weeks after laser-induced CNV in rats, Zarranz-Ventura et al [31] confirmed that inhibition of TGF-β can reduce the progression of CNV lesions, and Recalde et al [32] drew a similar conclusion. Yuan and Neufeld [38] found that whereas microglial cells do not express TGF-β 2 in normal optic nerve heads and rarely contain TGF-β 1 , they can express TGF-β 2 in glaucomatous optic nerve heads, and a few of them contain TGF-β 1 .…”

Section: Discussionmentioning

confidence: 88%

Behaviour of CD11b-Positive Cells in an Animal Model of Laser-Induced Choroidal Neovascularisation

Heiduschka

Alex

et al. 2017

Ophthalmologica

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Background/Aim: Immune cells, e.g. microglial cells of the retina, appear to be involved in pathological processes in neovascular age-related macular degeneration. Therefore, the purpose of this study was to immunohistochemically check the expression of various factors and cytokines by CD11b-positive (CD11b+) immune cells in an animal model of choroidal neovascularisation (CNV). Methods: We used the animal model of laser-induced CNV in mice. Eyes were isolated at 1, 4, 7, and 14 days after laser treatment. Cryosections were prepared and checked immunohistochemically for the presence of different growth factors and cytokines on microglial cells and other immune cells identified by CD11b immunoreactivity. Results: We found that the number of CD11b+ cells at the laser spots increased dramatically 4 days after laser treatment, the majority of them entering the laser spot most probably by migration. CD11b+ cells in the laser spot were positive for a variety of pro-angiogenic factors, such as PDGF-β, FGF-1, FGF-2, and TGF-β₁. They were also positive for some inflammatory cytokines, in particular TNF-α, IL-6, and CXCL1. In non-treated retinas, CD11b+ cells showed almost no immunoreactivity for these proteins. Conclusion: Microglial cells, macrophages, and other CD11b+ cells may promote the neovascularisation in the laser spot and show a moderate inflammatory behaviour. Immunoreactivity for most of these molecules was found to decrease during the time of observation. Modulation of immune cell activity may thus be a tool to reduce the extent of CNV.

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“…53,54 These peptides have shown an antagonist effect over TGFb-dependent processes in cellular cultures and a strong TGF-b inhibitory effect in different animal models. 23,[55][56][57] PD Fluid Exposure Model in Mice Female C57BL/6 mice between 12 and 16 weeks of age were used in this study (Harlan Interfauna Iberica, Barcelona, Spain). The experimental protocol used was in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals and approved by the Animal Ethics Committee of the Centro de Biología Molecular "Severo Ochoa."…”

Section: Reagentsmentioning

confidence: 99%

A Pathogenetic Role for Endothelin-1 in Peritoneal Dialysis-Associated Fibrosis

Busnadiego

Loureiro-Álvarez

Sandoval

et al. 2015

Journal of the American Society of Nephrology

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In patients undergoing peritoneal dialysis (PD), chronic exposure to nonphysiologic PD fluids elicits lowgrade peritoneal inflammation, leading to fibrosis and angiogenesis. Phenotype conversion of mesothelial cells into myofibroblasts, the so-called mesothelial-to-mesenchymal transition (MMT), significantly contributes to the peritoneal dysfunction related to PD. A number of factors have been described to induce MMT in vitro and in vivo, of which TGF-b1 is probably the most important. The vasoconstrictor peptide endothelin-1 (ET-1) is a transcriptional target of TGF-b1 and mediates excessive scarring and fibrosis in several tissues. This work studied the contribution of ET-1 to the development of peritoneal damage and failure in a mouse model of PD. ET-1 and its receptors were expressed in the peritoneal membrane and upregulated on PD fluid exposure. Administration of an ET receptor antagonist, either bosentan or macitentan, markedly attenuated PD-induced MMT, fibrosis, angiogenesis, and peritoneal functional decline. Adenovirus-mediated overexpression of ET-1 induced MMT in human mesothelial cells in vitro and promoted the early cellular events associated with peritoneal dysfunction in vivo. Notably, TGF-b1-blocking peptides prevented these actions of ET-1. Furthermore, a positive reciprocal relationship was observed between ET-1 expression and TGF-b1 expression in human mesothelial cells. These results strongly support a role for an ET-1/TGF-b1 axis as an inducer of MMT and subsequent peritoneal damage and fibrosis, and they highlight ET-1 as a potential therapeutic target in the treatment of PDassociated dysfunction.

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Transforming Growth Factor-Beta Inhibition Reduces Progression of Early Choroidal Neovascularization Lesions in Rats: P17 and P144 Peptides

Cited by 33 publications

References 37 publications

Transforming growth factor (TGF)-β signalling is increased in rheumatoid synovium but TGF-β blockade does not modify experimental arthritis

Transforming growth factor (TGF)-β signalling is increased in rheumatoid synovium but TGF-β blockade does not modify experimental arthritis

Behaviour of CD11b-Positive Cells in an Animal Model of Laser-Induced Choroidal Neovascularisation

A Pathogenetic Role for Endothelin-1 in Peritoneal Dialysis-Associated Fibrosis

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