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Huang D, Liu Z, Deng Y. Retinopathy of Prematurity (ROP): An Overview of Biomarkers in Various Samples for Prediction, Diagnosis, and Prognosis. Clin Ophthalmol 2025; 19:1515-1530. [PMID: 40357456 PMCID: PMC12067468 DOI: 10.2147/opth.s519292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Accepted: 04/22/2025] [Indexed: 05/15/2025] Open
Abstract
Retinopathy of Prematurity (ROP) is a proliferative retinal vascular disease marked by abnormal development of retinal vessels in low birth weight preterm infants. It is one of the leading causes of blindness in preterm infants. Current ROP screening methods impose high demands on both the equipment and the expertise of ophthalmologists, which limits their widespread application, particularly in secondary hospitals and remote areas. Thus, the identification of relevant biomarkers and the development of simpler detection methods are important and promising. Non-invasive or minimally invasive sampling methods, along with biomarkers possessing high sensitivity and specificity, could greatly enhance neonatal screening, facilitate early diagnosis, and improve prevention of blindness in preterm infants. This review provides relevant medical insights for clinical practice. This review explored, compares and analyzes various sampling sources. It compares and analyzes research on ROP-related biomarkers derived from these samples.
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Affiliation(s)
- Dan Huang
- Department of Ophthalmology Center, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of China
| | - ZhuoQi Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of China
| | - Yan Deng
- Department of Ophthalmology Center, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of China
- Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of China
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Wu HS, Huang HC, Chen IL. Analysis of Salivary Cytokines in Retinopathy of Prematurity. CHILDREN (BASEL, SWITZERLAND) 2025; 12:80. [PMID: 39857911 PMCID: PMC11764213 DOI: 10.3390/children12010080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 01/04/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025]
Abstract
BACKGROUND/OBJECTIVES This cohort study aimed to establish a correlation between salivary cytokines and retinopathy of prematurity (ROP) in premature neonates. Additionally, we sought to identify a minimally invasive method for cytokine detection in this population. METHODS We recruited premature neonates born at less than 34 weeks gestational age (GA), with no history of maternal or neonatal infections. Salivary samples were collected on their first (D1) and seventh (D7) days of life, and cytokine levels were measured using the MILLPLEXMAP Human multiplex assay. RESULTS A total of 125 neonates were included in the study, categorized into two groups based on the severity of ROP: None to Mild and Moderate to Severe. The salivary levels of interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), and tumor necrosis factor (TNF)-α on D1 and D7 were significantly higher in the Moderate to Severe ROP group compared to the None to Mild ROP group (p = 0.005, 0.004, 0.026, 0.018, 0.001, 0.007, 0.025, and 0.002, respectively). After adjusting for GA, the levels of IL-6 and VEGF on D7 were significantly elevated in the Moderate to Severe ROP group compared to the None to Mild ROP group (p = 0.024 and 0.016, respectively). CONCLUSIONS This study establishes a novel, non-invasive method for the early prediction of ROP in premature neonates by correlating salivary cytokine levels in early life with the subsequent development of ROP.
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Affiliation(s)
- Hwa-Shiu Wu
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 83301, Taiwan; (H.-S.W.); (H.-C.H.)
| | - Hsin-Chun Huang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 83301, Taiwan; (H.-S.W.); (H.-C.H.)
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Linkou 33302, Taiwan
| | - I-Lun Chen
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 83301, Taiwan; (H.-S.W.); (H.-C.H.)
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Linkou 33302, Taiwan
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Golubinskaya V, Nilsson H, Rydbeck H, Hellström W, Hellgren G, Hellström A, Sävman K, Mallard C. Cytokine and growth factor correlation networks associated with morbidities in extremely preterm infants. BMC Pediatr 2024; 24:723. [PMID: 39529072 PMCID: PMC11555815 DOI: 10.1186/s12887-024-05203-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/02/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Cytokines and growth factors (GF) have been implicated in the development of retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD). We hypothesize that even small coordinated changes in inflammatory proteins or GFs may reveal changes in underlying regulating mechanisms that do not induce obvious changes in concentration of individual proteins. We therefore applied correlation network analysis of serum factors to determine early characteristics of these conditions. METHODS Concentrations of 17 cytokines and five GFs were measured and analysed in blood samples from cord blood, on day one and during the following month in 72 extremely preterm infants. Spearman's correlation networks distinguishing BPD and severe ROP patients from non-affected were created. RESULTS Most cytokine concentrations correlated positively with each other and negatively with GFs. Very few individual cytokines differed between patients with and without ROP or BPD. However, networks of differently correlated serum factors were characteristic of the diseases and changed with time. In ROP networks, EPO, G-CSF and IL-8 (cord blood), BDNF and VEGF-A (first month) were prominent. In BPD networks, IL-1β, IGF-1 and IL-17 (day one) were noted. CONCLUSIONS Network analysis identifies protein signatures related to ROP or BPD in extremely preterm infants. The identified interactions between serum factors are not evident from the analysis of their individual levels, but may reveal underlying pathophysiological mechanisms in the development of these diseases.
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Affiliation(s)
- Veronika Golubinskaya
- Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska Academy, 432 40530, Gothenburg, Sweden.
| | - Holger Nilsson
- Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska Academy, 432 40530, Gothenburg, Sweden
| | - Halfdan Rydbeck
- Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska Academy, 432 40530, Gothenburg, Sweden
- The Bioinformatics Core Facility at the University of Gothenburg, Gothenburg, Sweden
| | - William Hellström
- Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden
| | - Gunnel Hellgren
- Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden
| | - Ann Hellström
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden
| | - Karin Sävman
- Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, Sahlgrenska Academy, Gothenburg, Sweden
- Department of Neonatology, Region Västra Götaland, The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Carina Mallard
- Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska Academy, 432 40530, Gothenburg, Sweden
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Sjöbom U, Hellqvist T, Humayun J, Nilsson AK, Gyllensten H, Hellström A, Löfqvist C. Circulating VEGF-A Levels in Relation to Retinopathy of Prematurity and Treatment Effects: A Systematic Review and Meta-Analysis. OPHTHALMOLOGY SCIENCE 2024; 4:100548. [PMID: 39184225 PMCID: PMC11342886 DOI: 10.1016/j.xops.2024.100548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 03/18/2024] [Accepted: 04/29/2024] [Indexed: 08/27/2024]
Abstract
Topic Retinopathy of prematurity (ROP) is a severe retinal vascular disorder affecting preterm infants, potentially leading to retinal detachment and blindness. This review aims to elucidate the relationship between systemic VEGF levels and ROP. Clinical Relevance This systematic review aims to consolidate evidence from available studies to guide future research and inform clinical practice. In particular, the role of circulating VEGF-A levels in predicting ROP onset and progression, and evaluating the impact of anti-VEGF therapy on these levels, is crucial in ensuring efficacy and safety in patient care. Methods Scopus and PubMed were searched to identify studies investigating circulating VEGF-gene products in ROP patients using immunologic assays. Two authors independently screened the literature and extracted data, employing a random-effects meta-analysis to compare VEGF levels as the ratio of means between ROP patients and controls before and after treatment, heterogeneity was reported by I2-statistics. Risks of bias and publication bias were assessed using Quality Assessment of Diagnostic Accuracy Studies-2 and funnel plots/Egger's tests, respectively. Results Out of 941 papers, 54 were included, with 26 providing posttreatment data and 31 providing biomarker data. Findings show a significant decrease in VEGF-A levels in the first week after ROP treatment (ratio of means [95% confidence interval] 0.34 [0.25-0.45], I2 = 97%, 17 publications). Anti-VEGF therapy showed a significantly more pronounced decrease (0.31 [0.25-0.38], I2 = 40%, 7 publications) than laser treatment in the first week after treatment (0.77 [0.61-0.97], I2 = 42%, 2 publications, subgroup difference, P < 0.01), among studies with a low risk of bias. Serum samples demonstrated a more marked decrease in VEGF-A than plasma (subgroup difference P < 0.01). However, the use of blood VEGF-A concentration as a biomarker for ROP prediction has shown inconsistent trends. The risk of bias mainly stems from unclear patient selection and lack of sample timing or analytical method details. Conclusion While anti-VEGF treatment significantly reduced blood VEGF-A levels in the first week post-ROP treatment, blood VEGF-A levels did not consistently predict ROP development. Heterogeneity in the results underscores the need for optimized analytical methods and emphasizes the importance of considering individual variation in VEGF-A concentrations independent of ROP diagnosis. Financial Disclosures The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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Affiliation(s)
- Ulrika Sjöbom
- Learning and Leadership for Health Care Professionals At the Institute of Health and Care Science at Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Neuroscience At the Institution of Neuroscience and Physiology at Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Tove Hellqvist
- Department of Clinical Neuroscience At the Institution of Neuroscience and Physiology at Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Jhangir Humayun
- Learning and Leadership for Health Care Professionals At the Institute of Health and Care Science at Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Anders K. Nilsson
- Department of Clinical Neuroscience At the Institution of Neuroscience and Physiology at Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Hanna Gyllensten
- Learning and Leadership for Health Care Professionals At the Institute of Health and Care Science at Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Ann Hellström
- Department of Clinical Neuroscience At the Institution of Neuroscience and Physiology at Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Chatarina Löfqvist
- Learning and Leadership for Health Care Professionals At the Institute of Health and Care Science at Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Neuroscience At the Institution of Neuroscience and Physiology at Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
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Dayoub AS, Acharya E, Dibas A, Jones HP, Acharya S. Novel Small Molecules with Anti-Inflammatory and Anti-Angiogenic Activity in a Mouse Model of Oxygen-Induced Retinopathy. Cells 2024; 13:1371. [PMID: 39195259 PMCID: PMC11353024 DOI: 10.3390/cells13161371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 08/10/2024] [Accepted: 08/14/2024] [Indexed: 08/29/2024] Open
Abstract
Retinopathy of prematurity (ROP) has a dual-phase disease pathology; in phase 1, hyperoxia-induced vaso-obliteration occurs in the retinal vasculature due to increased oxidative stress (OS) and inflammation, followed by phase 2, where hypoxia increases the overproduction of growth factors, inducing retinal neovascularization. Toll-like receptor 2 and -4 (TLR2 and TLR4) overactivation, hyper-inflammation, macrophages, and neutrophil infiltration contribute to the developing ROP. AVR-121 and AVR-123 are novel classes of small-molecule dual inhibitors of TLR2/4 tested in a human leukemia monocytic cell line (THP-1) and cord-blood-derived mononuclear cells (CBMCs). Both compounds inhibited TLR2/4 signaling-related inflammatory cytokines in THP-1 cells and inhibited VEGF-induced neovascularization in human retinal endothelial cells (HRECs), which are hallmarks of ROP. In an oxygen-induced retinopathy (OIR) murine model, the intraperitoneal injection of AVR-123 in the hyperoxia phase (P7-P12) or a nanosuspension eyedrop of AVR-123 in the hypoxic phase (P12-P17) significantly reduced vaso-obliteration, angiogenesis, and inflammatory cytokine profiles while not inhibiting the necessary growth factor VEGF in the juvenile mouse eyes. The results are consistent with our hypothesis that targeting the dual TLR2/4 pathway will reduce inflammation, angiogenesis, and vaso-obliteration in vitro and in vivo and reduce cytotoxic immune cells. AVR-123 has the potential to be developed as a therapy for ROP.
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Affiliation(s)
- Adam S. Dayoub
- AyuVis Research Inc., Fort Worth, TX 76107, USA; (A.S.D.)
| | - Eesha Acharya
- AyuVis Research Inc., Fort Worth, TX 76107, USA; (A.S.D.)
| | - Adnan Dibas
- The North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Harlan P. Jones
- The North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Suchismita Acharya
- AyuVis Research Inc., Fort Worth, TX 76107, USA; (A.S.D.)
- The North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
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Hou Y, Tang Y, Cai S. Advances in the study of microparticles in diabetic retinopathy. Postgrad Med J 2024; 100:626-634. [PMID: 38572927 DOI: 10.1093/postmj/qgae046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 03/07/2024] [Accepted: 03/16/2024] [Indexed: 04/05/2024]
Abstract
Diabetic retinopathy (DR) is one of the common diabetic microangiopathies, which severely impairs vision in diabetic population. The underlying mechanisms regarding the development of DR are not fully understood, and there is a lack of biomarkers to guide clinical, assessment of disease progression. Recently researchers have found that microparticles (MP) and its bioactive molecules are involved in the development of DR. MP is widely distributed in the circulation and can exert autocrine and paracrine benefits in intercellular signalling, provide a catalytic platform for the thrombospondin complex to promote coagulation, and promote the accumulation of reactive oxygen species to cause endothelial damage. MP interacts with advanced glycosylation end products (AGE) and AGE receptor (RAGE) to activate inflammatory pathways. MP carries a variety of miRNAs that regulate the vascular endothelial growth factor generation pathway. MP has also been applied to the exploration of mesenchymal stromal cell replacement therapy to treat DR. In a word, MP provides new ideas for the study of DR. MP has emerged as a marker to assess the progression of DR. As a potential therapeutic target, MP also has considerable research value.
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Affiliation(s)
- Yifeng Hou
- Department of Ophthalmology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
- Guizhou Eye Hospital, Zunyi 563003, Guizhou Province, China
- Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi 563003, Guizhou Province, China
- Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Yun Tang
- Department of Ophthalmology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
- Guizhou Eye Hospital, Zunyi 563003, Guizhou Province, China
- Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi 563003, Guizhou Province, China
- Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Shanjun Cai
- Department of Ophthalmology, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, Guizhou Province, China
- Guizhou Eye Hospital, Zunyi 563003, Guizhou Province, China
- Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi 563003, Guizhou Province, China
- Special Key Laboratory of Ocular Diseases of Guizhou Province, Zunyi Medical University, Zunyi 563000, Guizhou Province, China
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Baba T, Uotani R, Inata K, Sasaki SI, Shimizu Y, Miura M, Inoue Y, Miyazaki D. Tear fluid cytokine analysis: a non-invasive approach for assessing retinopathy of prematurity severity. Jpn J Ophthalmol 2024:10.1007/s10384-024-01084-0. [PMID: 38985404 DOI: 10.1007/s10384-024-01084-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 05/29/2024] [Indexed: 07/11/2024]
Abstract
PURPOSE To determine whether there is a significant association between inflammatory cytokines in the tear fluid and the severity of Retinopathy of Prematurity (ROP). STUDY DESIGN Retrospective cohort study. METHODS The cytokine levels in tear fluids were determined in 34 eyes with ROP and 18 eyes without ROP. There were 15 eyes with severe ROP requiring treatment and 19 eyes with mild ROP not requiring treatment. For severe ROP eyes, tear fluids were collected before treatment. RESULTS Significantly higher levels of CCL2 and vascular endothelial growth factor (VEGF) were detected in eyes with severe ROP compared to eyes with mild ROP and no ROP. When assessed for cytokine levels that discriminate each disease group, CCL2 showed a significant odds ratio of 1.76 for severity change (/quintile, P = 0.032, after adjusting for birth weight). Correlation analysis showed that birth weight correlated with IL-1α levels, and decreased weight gain increased IFN-γ levels. We next determined tear fluid cytokines which discriminate severe ROP using receiver operating characteristics' analysis. We found that combination of higher CCL2 levels, higher VEGF levels, and lower IFN-γ levels in the tear fluid had a stronger predictive value for severe ROP (area under curve, 0.85). CONCLUSION The levels of CCL2, VEGF, and IFN-γ in tear fluid may serve as useful biomarkers for assessing the severity of ROP.
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Affiliation(s)
- Takashi Baba
- Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, 36-1 Nishicho, Yonago, 683-8504, Japan.
| | - Ryu Uotani
- Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, 36-1 Nishicho, Yonago, 683-8504, Japan
| | - Kodai Inata
- Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, 36-1 Nishicho, Yonago, 683-8504, Japan
| | - Shin-Ichi Sasaki
- Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, 36-1 Nishicho, Yonago, 683-8504, Japan
| | - Yumiko Shimizu
- Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, 36-1 Nishicho, Yonago, 683-8504, Japan
| | - Mazumi Miura
- Division of Pediatrics and Perinatology, Faculty of Medicine, Tottori University, Yonago, Japan
- Department of Pediatrics, Kawasaki Medical School, Kurashiki, Japan
| | - Yoshitsugu Inoue
- Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, 36-1 Nishicho, Yonago, 683-8504, Japan
| | - Dai Miyazaki
- Division of Ophthalmology and Visual Science, Faculty of Medicine, Tottori University, 36-1 Nishicho, Yonago, 683-8504, Japan
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Mckinnon K, Conole ELS, Vaher K, Hillary RF, Gadd DA, Binkowska J, Sullivan G, Stevenson AJ, Corrigan A, Murphy L, Whalley HC, Richardson H, Marioni RE, Cox SR, Boardman JP. Epigenetic scores derived in saliva are associated with gestational age at birth. Clin Epigenetics 2024; 16:84. [PMID: 38951914 PMCID: PMC11218140 DOI: 10.1186/s13148-024-01701-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 06/22/2024] [Indexed: 07/03/2024] Open
Abstract
BACKGROUND Epigenetic scores (EpiScores), reflecting DNA methylation (DNAm)-based surrogates for complex traits, have been developed for multiple circulating proteins. EpiScores for pro-inflammatory proteins, such as C-reactive protein (DNAm CRP), are associated with brain health and cognition in adults and with inflammatory comorbidities of preterm birth in neonates. Social disadvantage can become embedded in child development through inflammation, and deprivation is overrepresented in preterm infants. We tested the hypotheses that preterm birth and socioeconomic status (SES) are associated with alterations in a set of EpiScores enriched for inflammation-associated proteins. RESULTS In total, 104 protein EpiScores were derived from saliva samples of 332 neonates born at gestational age (GA) 22.14 to 42.14 weeks. Saliva sampling was between 36.57 and 47.14 weeks. Forty-three (41%) EpiScores were associated with low GA at birth (standardised estimates |0.14 to 0.88|, Bonferroni-adjusted p-value < 8.3 × 10-3). These included EpiScores for chemokines, growth factors, proteins involved in neurogenesis and vascular development, cell membrane proteins and receptors, and other immune proteins. Three EpiScores were associated with SES, or the interaction between birth GA and SES: afamin, intercellular adhesion molecule 5, and hepatocyte growth factor-like protein (standardised estimates |0.06 to 0.13|, Bonferroni-adjusted p-value < 8.3 × 10-3). In a preterm subgroup (n = 217, median [range] GA 29.29 weeks [22.14 to 33.0 weeks]), SES-EpiScore associations did not remain statistically significant after adjustment for sepsis, bronchopulmonary dysplasia, necrotising enterocolitis, and histological chorioamnionitis. CONCLUSIONS Low birth GA is substantially associated with a set of EpiScores. The set was enriched for inflammatory proteins, providing new insights into immune dysregulation in preterm infants. SES had fewer associations with EpiScores; these tended to have small effect sizes and were not statistically significant after adjusting for inflammatory comorbidities. This suggests that inflammation is unlikely to be the primary axis through which SES becomes embedded in the development of preterm infants in the neonatal period.
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Affiliation(s)
- Katie Mckinnon
- Centre for Reproductive Health, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Eleanor L S Conole
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK
| | - Kadi Vaher
- Centre for Reproductive Health, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Robert F Hillary
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Danni A Gadd
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Justyna Binkowska
- Centre for Reproductive Health, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Gemma Sullivan
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Anna J Stevenson
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Amy Corrigan
- Centre for Reproductive Health, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Lee Murphy
- Edinburgh Clinical Research Facility, University of Edinburgh, Edinburgh, UK
| | - Heather C Whalley
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Hilary Richardson
- School of Philosophy, Psychology, and Language Sciences, University of Edinburgh, Edinburgh, UK
| | - Riccardo E Marioni
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Simon R Cox
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, UK
| | - James P Boardman
- Centre for Reproductive Health, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh, EH16 4UU, UK.
- Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
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Ling XC, Huang PH, Chen HC, Hsueh YJ, Lee CW, Lien R, Lee CC, Chu SM, Chen KJ, Hwang YS, Lai CC, Chiang MC, Wu WC. Association of serum levels of inflammatory cytokines with retinopathy of prematurity in preterm infants. Front Pediatr 2024; 11:1195904. [PMID: 38259597 PMCID: PMC10800500 DOI: 10.3389/fped.2023.1195904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 12/19/2023] [Indexed: 01/24/2024] Open
Abstract
Introduction Retinopathy of prematurity (ROP) is a retinal vascular developmental disease associated with risks factors such as supplementary oxygen use or low birth weight/early gestational age. Multiple studies have reported associations between ROP and systemic inflammation. In this study, we investigated serum cytokines associated with ROP development and severity and assessed their applicability as potential biomarkers of ROP. Methods This prospective study was conducted at an institutional referral center between 2019 and 2021. To measure the serum levels of 40 inflammatory cytokines in eligible premature patients, we collected their serum samples during the enrollment of patients or the intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents and after 2 and 4 weeks. Results Fifty patients were enrolled. In patients with type 1 ROP who received anti-VEGF agents (n = 22), the levels of serum intercellular adhesion molecule-1 decreased significantly (p < 0.05) at 4 weeks compared with the baseline level, whereas those of serum granulocyte-macrophage colony-stimulating factor increased significantly (p < 0.05). In patients with ROP who did not require any treatment (n = 14), no significant change was noted in the level of any of the 40 inflammatory cytokines. In control infants without ROP (n = 14), the serum levels of tumor necrosis factor-α, interleukin (IL)-15, and IL-12p40 increased significantly (p < 0.05) at 4 weeks. The changes in the levels of serum inflammatory cytokines did not vary significantly among the aforementioned three groups. A generalized estimating equation indicated that zone 1 ROP, stage 3 ROP, older postmenstrual age, respiratory distress syndrome, necrotizing enterocolitis, and sepsis were associated with the changes in serum cytokine levels. Conclusions Although significant changes (compared with baseline) were observed in the serum levels of certain inflammatory cytokines in patients with type 1 ROP and infants without ROP, no significant difference in cytokine level fluctuations were noted among the three groups. Changes in serum inflammatory cytokine levels may not predict ROP development or severity. Additional comprehensive studies are warranted to establish their definitive role and significance in ROP, emphasizing the need for continued research in this area.
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Affiliation(s)
- Xiao Chun Ling
- Department of Ophthalmology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Pin-Hsuan Huang
- Center for Big Data Analytics and Statistics, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Hung-Chi Chen
- Department of Ophthalmology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Jen Hsueh
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
| | - Chia-Wen Lee
- Department of Ophthalmology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Reyin Lien
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Neonatology, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chien-Chung Lee
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Neonatology, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Shih-Ming Chu
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Neonatology, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Kuan-Jen Chen
- Department of Ophthalmology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yih-Shiou Hwang
- Department of Ophthalmology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chi-Chun Lai
- Department of Ophthalmology, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Ming-Chou Chiang
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Neonatology, Department of Pediatrics, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wei-Chi Wu
- Department of Ophthalmology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
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10
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Hoyek S, Cruz NFSD, Patel NA, Al-Khersan H, Fan KC, Berrocal AM. Identification of novel biomarkers for retinopathy of prematurity in preterm infants by use of innovative technologies and artificial intelligence. Prog Retin Eye Res 2023; 97:101208. [PMID: 37611892 DOI: 10.1016/j.preteyeres.2023.101208] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/16/2023] [Accepted: 08/18/2023] [Indexed: 08/25/2023]
Abstract
Retinopathy of prematurity (ROP) is a leading cause of preventable vision loss in preterm infants. While appropriate screening is crucial for early identification and treatment of ROP, current screening guidelines remain limited by inter-examiner variability in screening modalities, absence of local protocol for ROP screening in some settings, a paucity of resources and an increased survival of younger and smaller infants. This review summarizes the advancements and challenges of current innovative technologies, artificial intelligence (AI), and predictive biomarkers for the diagnosis and management of ROP. We provide a contemporary overview of AI-based models for detection of ROP, its severity, progression, and response to treatment. To address the transition from experimental settings to real-world clinical practice, challenges to the clinical implementation of AI for ROP are reviewed and potential solutions are proposed. The use of optical coherence tomography (OCT) and OCT angiography (OCTA) technology is also explored, providing evaluation of subclinical ROP characteristics that are often imperceptible on fundus examination. Furthermore, we explore several potential biomarkers to reduce the need for invasive procedures, to enhance diagnostic accuracy and treatment efficacy. Finally, we emphasize the need of a symbiotic integration of biologic and imaging biomarkers and AI in ROP screening, where the robustness of biomarkers in early disease detection is complemented by the predictive precision of AI algorithms.
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Affiliation(s)
- Sandra Hoyek
- Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Natasha F S da Cruz
- Bascom Palmer Eye Institute, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA
| | - Nimesh A Patel
- Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | - Hasenin Al-Khersan
- Bascom Palmer Eye Institute, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA
| | - Kenneth C Fan
- Bascom Palmer Eye Institute, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA
| | - Audina M Berrocal
- Bascom Palmer Eye Institute, University of Miami Leonard M. Miller School of Medicine, Miami, FL, USA.
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11
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Vinekar A, Nair AP, Sinha S, Vaidya T, Shetty R, Ghosh A, Sethu S. Early detection and correlation of tear fluid inflammatory factors that influence angiogenesis in premature infants with and without retinopathy of prematurity. Indian J Ophthalmol 2023; 71:3465-3472. [PMID: 37870008 PMCID: PMC10752326 DOI: 10.4103/ijo.ijo_3407_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 06/05/2023] [Accepted: 06/13/2023] [Indexed: 10/24/2023] Open
Abstract
Purpose To measure the levels of inflammatory factors in tear fluid of pre-term infants with and without retinopathy of prematurity (ROP). Methods The cross-sectional pilot study included 29 pre-term infants undergoing routine ROP screening. Pre-term infants were grouped as those without ROP (no ROP; n = 14) and with ROP (ROP; n = 15). Sterile Schirmer's strips were used to collect the tear fluid from pre-term infants. Inflammatory factors such as interleukin (IL)-6, IL-8, MCP1 (Monocyte Chemoattractant Protein 1; CCL2), RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted; CCL5), and soluble L-selectin (sL-selectin) were measured by cytometric bead array using a flow cytometer. Results Birth weight (BW) and gestation age (GA) were significantly (P < 0.05) lower in pre-term infants with ROP compared with those without ROP. Higher levels of RANTES (P < 0.05) and IL-8 (P = 0.09) were observed in the tear fluid of pre-term infants with ROP compared with those without ROP. Lower levels of tear fluid IL-6 (P = 0.14) and sL-selectin (P = 0.18) were measured in pre-term infants with ROP compared with those without ROP. IL-8 and RANTES were significantly (P < 0.05) higher in the tear fluid of pre-term infants with stage 3 ROP compared with those without ROP. Tear fluid RANTES level was observed to be inversely associated with GA and BW of pre-term infants with ROP and not in those without ROP. Furthermore, the area under the curve and odds ratio analysis demonstrated the relevance of RANTES/BW (AUC = 0.798; OR-7.2) and RANTES/MCP1 (AUC = 0.824; OR-6.8) ratios in ROP. Conclusions Distinct changes were observed in the levels of tear inflammatory factors in ROP infants. The status of RANTES in ROP suggests its possible role in pathobiology and warrants further mechanistic studies to harness it in ROP screening and management.
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Affiliation(s)
- Anand Vinekar
- Department of Pediatric Retina, Narayana Nethralaya Eye Institute, Bangaluru, Karnataka, India
| | | | - Shivani Sinha
- Department of Pediatric Retina, Narayana Nethralaya Eye Institute, Bangaluru, Karnataka, India
| | - Tanuja Vaidya
- GROW Research Laboratory, Narayana Nethralaya Foundation, Bengaluru, Karnataka, India
| | - Rohit Shetty
- Division of Cornea and Refractive Surgery, Narayana Nethralaya Eye Institute, Bengaluru, Karnataka, India
| | - Arkasubhra Ghosh
- GROW Research Laboratory, Narayana Nethralaya Foundation, Bengaluru, Karnataka, India
| | - Swaminathan Sethu
- GROW Research Laboratory, Narayana Nethralaya Foundation, Bengaluru, Karnataka, India
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12
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Yeh JL, Kuo CH, Shih PW, Hsu JH, I-Chen P, Huang YH. Xanthine derivative KMUP-1 ameliorates retinopathy. Biomed Pharmacother 2023; 165:115109. [PMID: 37406513 DOI: 10.1016/j.biopha.2023.115109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 06/17/2023] [Accepted: 06/28/2023] [Indexed: 07/07/2023] Open
Abstract
Retinal neovascularization (RNV) and cell apoptosis observed in retinopathy are the most common cause of vision loss worldwide. Increasing vascular endothelial growth factor (VEGF), which was driven by hypoxia or inflammation, would result in RNV. This study investigated the anti-inflammatory and anti-apoptotic xanthine-based derivative KMUP-1 on hypoxia-induced conditions in vitro and in vivo. In the oxygen-induced retinopathy animal model, KMUP-1 mitigated vaso-obliteration and neovascularization. In the cell model of hypoxic endothelium cultured at 1% O2, KMUP-1 inhibited endothelial migration and tube formation and had no cytotoxic effect on cell growth. Upregulation of pro-angiogenic factors, HIF-1α and VEGF, and pro-inflammatory cytokines, IL-1β and TNF-α, expression in the retinal-derived endothelial cells, RF/6 A cells, upon hypoxia stimulation, was suppressed by KMUP-1 treatment. RF/6 A cells treated with KMUP-1 showed a reduction of PI3K/Akt, ERK, and RhoA/ROCKs signaling pathways and induction of protective pathways such as eNOS and soluble guanylyl cyclase at 1% O2. Furthermore, KMUP-1 decreased the expression of VEGF, ICAM-1, TNF-α, and IL-1β and increased the BCL-2/BAX ratio in the oxygen-induced retinopathy mouse retina samples. In conclusion, the results of this study suggest that KMUP-1 has potential therapeutic value in retinopathy due to its triple effects on anti-angiogenesis, anti-inflammation, and anti-apoptosis in hypoxic endothelium.
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Affiliation(s)
- Jwu-Lai Yeh
- Department of Pharmacology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, 80424 Kaohsiung, Taiwan
| | - Cheng-Hsiang Kuo
- International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan 70101, Taiwan
| | - Po-Wen Shih
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jong-Hau Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan; Department of Pediatrics, School of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Peng I-Chen
- Department of Ophthalmology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Yi-Hsun Huang
- Department of Ophthalmology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
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13
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Obata S, Matsumoto R, Kakinoki M, Sawada O, Sawada T, Saishin Y, Yanagi T, Maruo Y, Ohji M. Association between treatment for retinopathy of prematurity and blood monocyte counts. Jpn J Ophthalmol 2023:10.1007/s10384-023-00992-x. [PMID: 37140746 DOI: 10.1007/s10384-023-00992-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 03/15/2023] [Indexed: 05/05/2023]
Abstract
PURPOSE To investigate blood monocyte counts as a risk factor for retinopathy of prematurity (ROP) treatment. DESIGN Retrospective cohort study. METHODS Infants who underwent ROP screening at Shiga University of Medical Science Hospital between January, 2011 and July, 2021 were included in this study. Screening criteria were a gestational age (GA) < 32 weeks or birth weight (BW) < 1500 g. The week with the largest difference in monocyte counts between the infants with and without type 1 ROP determined based on the effect size. Multivariate logistic regression analysis was applied to investigate whether the monocyte counts constituted an independent risk factor for type 1 ROP. The objective variable was type 1 ROP, and the explanatory variables were GA, BW, infants' infection, and Apgar score at 1 min and monocyte counts in the week with the largest monocyte-counts difference between the with- and without type 1 ROP groups. RESULTS In total, 231 infants met the inclusion criteria. The monocyte counts in the fourth week after birth (4w MONO) exhibited the largest difference between infants with and without type 1 ROP. The analysis was performed on 198 infants, excluding 33 infants without 4w MONO data. Thirty-one infants had type 1 ROP, whereas 167 infants did not. BW and 4w MONO were significantly associated with type 1 ROP (odds ratio: 0.52 and 3.9, P < .001 and 0.004, respectively). CONCLUSIONS The 4w MONO was an independent risk factor for type 1 ROP and may be useful in follow-up of infants with ROP.
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Affiliation(s)
- Shumpei Obata
- Department of Ophthalmology, Shiga University of Medical Science, Shiga, Japan.
| | - Riko Matsumoto
- Department of Ophthalmology, Shiga University of Medical Science, Shiga, Japan
| | - Masashi Kakinoki
- Department of Ophthalmology, Shiga University of Medical Science, Shiga, Japan
| | - Osamu Sawada
- Department of Ophthalmology, Shiga University of Medical Science, Shiga, Japan
| | - Tomoko Sawada
- Department of Ophthalmology, Shiga University of Medical Science, Shiga, Japan
| | - Yoshitsugu Saishin
- Department of Ophthalmology, Shiga University of Medical Science, Shiga, Japan
| | - Takahide Yanagi
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
| | - Yoshihiro Maruo
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
| | - Masahito Ohji
- Department of Ophthalmology, Shiga University of Medical Science, Shiga, Japan
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14
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Deliyanti D, Figgett WA, Gebhardt T, Trapani JA, Mackay F, Wilkinson-Berka JL. CD8 + T Cells Promote Pathological Angiogenesis in Ocular Neovascular Disease. Arterioscler Thromb Vasc Biol 2023; 43:522-536. [PMID: 36794587 DOI: 10.1161/atvbaha.122.318079] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
Abstract
BACKGROUND CD4+ (cluster of differentation) and CD8+ T cells are increased in the ocular fluids of patients with neovascular retinopathy, yet their role in the disease process is unknown. METHODS We describe how CD8+ T cells migrate into the retina and contribute to pathological angiogenesis by releasing cytokines and cytotoxic factors. RESULTS In oxygen-induced retinopathy, flow cytometry revealed the numbers of CD4+ and CD8+ T cells were increased in blood, lymphoid organs, and retina throughout the development of neovascular retinopathy. Interestingly, the depletion of CD8+ T cells but not CD4+ T cells reduced retinal neovascularization and vascular leakage. Using reporter mice expressing gfp (green fluorescence protein) in CD8+ T cells, these cells were localized near neovascular tufts in the retina, confirming that CD8+ T cells contribute to the disease. Furthermore, the adoptive transfer of CD8+ T cells deficient in TNF (tumor necrosis factor), IFNγ (interferon gamma), Prf (perforin), or GzmA/B (granzymes A/B) into immunocompetent Rag1-/- mice revealed that CD8+ T cells mediate retinal vascular disease via these factors, with TNF influencing all aspects of vascular pathology. The pathway by which CD8+ T cells migrate into the retina was identified as CXCR3 (C-X-C motif chemokine receptor 3) with the CXCR3 blockade reducing the number of CD8+ T cells within the retina and retinal vascular disease. CONCLUSIONS We discovered that CXCR3 is central to the migration of CD8+ T cells into the retina as the CXCR3 blockade reduced the number of CD8+ T cells within the retina and vasculopathy. This research identified an unappreciated role for CD8+ T cells in retinal inflammation and vascular disease. Reducing CD8+ T cells via their inflammatory and recruitment pathways is a potential treatment for neovascular retinopathies.
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Affiliation(s)
- Devy Deliyanti
- Department of Anatomy and Physiology, School of Biomedical Sciences (D.D., J.L.W.-B.), University of Melbourne, Parkville, Victoria, Australia
- Department of Diabetes, Monash University, Melbourne, Victoria, Australia (D.D., J.L.W.-B.)
| | - William A Figgett
- Department of Microbiology and Immunology, School of Biomedical Sciences, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria, Australia (W.A.F.)
- Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia (W.A.F., T.G.)
| | - Thomas Gebhardt
- Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia (W.A.F., T.G.)
| | - Joseph A Trapani
- Sir Peter MacCallum Department of Oncology (J.A.T.), University of Melbourne, Parkville, Victoria, Australia
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia (J.A.T.)
| | - Fabienne Mackay
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (F.M.)
| | - Jennifer L Wilkinson-Berka
- Department of Anatomy and Physiology, School of Biomedical Sciences (D.D., J.L.W.-B.), University of Melbourne, Parkville, Victoria, Australia
- Department of Diabetes, Monash University, Melbourne, Victoria, Australia (D.D., J.L.W.-B.)
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15
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Fevereiro-Martins M, Marques-Neves C, Guimarães H, Bicho M. Retinopathy of prematurity: A review of pathophysiology and signaling pathways. Surv Ophthalmol 2023; 68:175-210. [PMID: 36427559 DOI: 10.1016/j.survophthal.2022.11.007] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 11/15/2022] [Accepted: 11/18/2022] [Indexed: 11/25/2022]
Abstract
Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina and a leading cause of visual impairment and childhood blindness worldwide. The disease is characterized by an early stage of retinal microvascular degeneration, followed by neovascularization that can lead to subsequent retinal detachment and permanent visual loss. Several factors play a key role during the different pathological stages of the disease. Oxidative and nitrosative stress and inflammatory processes are important contributors to the early stage of ROP. Nitric oxide synthase and arginase play important roles in ischemia/reperfusion-induced neurovascular degeneration. Destructive neovascularization is driven by mediators of the hypoxia-inducible factor pathway, such as vascular endothelial growth factor and metabolic factors (succinate). The extracellular matrix is involved in hypoxia-induced retinal neovascularization. Vasorepulsive molecules (semaphorin 3A) intervene preventing the revascularization of the avascular zone. This review focuses on current concepts about signaling pathways and their mediators, involved in the pathogenesis of ROP, highlighting new potentially preventive and therapeutic modalities. A better understanding of the intricate molecular mechanisms underlying the pathogenesis of ROP should allow the development of more effective and targeted therapeutic agents to reduce aberrant vasoproliferation and facilitate physiological retinal vascular development.
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Affiliation(s)
- Mariza Fevereiro-Martins
- Laboratório de Genética and Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, Portugal; Instituto de Investigação Científica Bento da Rocha Cabral, Lisboa, Portugal; Departamento de Oftalmologia, Hospital Cuf Descobertas, Lisboa, Portugal.
| | - Carlos Marques-Neves
- Centro de Estudos das Ci.¼ncias da Visão, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
| | - Hercília Guimarães
- Departamento de Ginecologia-Obstetrícia e Pediatria, Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
| | - Manuel Bicho
- Laboratório de Genética and Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, Portugal; Instituto de Investigação Científica Bento da Rocha Cabral, Lisboa, Portugal.
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16
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Sakai A, Tagami M, Katsuyama-Yoshikawa A, Misawa N, Haruna Y, Azumi A, Honda S. Relationship between Vitreous IL-6 Levels, Gender Differences and C-Reactive Protein (CRP) in a Blood Sample of Posterior Uveitis. J Clin Med 2023; 12:jcm12051720. [PMID: 36902507 PMCID: PMC10003048 DOI: 10.3390/jcm12051720] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/08/2023] [Accepted: 02/19/2023] [Indexed: 02/24/2023] Open
Abstract
This study retrospectively determined the relationship between vitreous IL-6 levels and clinical and laboratory data collected from uveitis patients. We examined an unknown cause of posterior uveitis, collecting vitreous fluid to investigate vitreous IL-6 levels. The samples were analyzed in consideration of clinical and laboratory factors, such as the male/female ratio. The present study included 82 eyes from 77 patients with a mean age of 66.20 ± 15.41 years. The IL-6 concentrations of the vitreous specimens were 6255.0 ± 14,108.3 pg/mL in males and 277.6 ± 746.3 pg/mL in females, which was found to be a statistically significant difference (p = 0.048) (n = 82). There was also a statistically significant correlation between vitreous IL-6 concentrations, serum C-reactive protein (CRP) value and white blood cell counts (WBCs) (n = 82). In multivariate analysis, vitreous IL-6 levels were significantly correlated with gender and CRP in all cases (p = 0.048 and p < 0.01, respectively) and were also significantly correlated with CRP in non-infectious uveitis (p < 0.01). In infectious uveitis, there were no significant differences between IL-6 level and several variables. Vitreous IL-6 concentrations were higher in males than in females in all cases. In non-infectious uveitis, vitreous IL-6 levels were correlated with serum CRP. These results might suggest that intraocular IL-6 levels depend on gender differences in posterior uveitis, and intraocular IL-6 levels in non-infectious uveitis may reflect systemic inflammations, including increased serum CRP.
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Affiliation(s)
- Atsushi Sakai
- Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
| | - Mizuki Tagami
- Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
- Correspondence: ; Tel.: +81-6-6645-3867; Fax: +81-6645-3867
| | | | - Norihiko Misawa
- Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
| | - Yusuke Haruna
- Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
| | - Atsushi Azumi
- Department of Ophthalmology, Kobe Kaisei Hospital, Kobe 657-0068, Japan
| | - Shigeru Honda
- Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan
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17
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Systemic Cytokines in Retinopathy of Prematurity. J Pers Med 2023; 13:jpm13020291. [PMID: 36836525 PMCID: PMC9966226 DOI: 10.3390/jpm13020291] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 01/30/2023] [Accepted: 01/30/2023] [Indexed: 02/09/2023] Open
Abstract
Retinopathy of prematurity (ROP), a vasoproliferative vitreoretinal disorder, is the leading cause of childhood blindness worldwide. Although angiogenic pathways have been the main focus, cytokine-mediated inflammation is also involved in ROP etiology. Herein, we illustrate the characteristics and actions of all cytokines involved in ROP pathogenesis. The two-phase (vaso-obliteration followed by vasoproliferation) theory outlines the evaluation of cytokines in a time-dependent manner. Levels of cytokines may even differ between the blood and the vitreous. Data from animal models of oxygen-induced retinopathy are also valuable. Although conventional cryotherapy and laser photocoagulation are well established and anti-vascular endothelial growth factor agents are available, less destructive novel therapeutics that can precisely target the signaling pathways are required. Linking the cytokines involved in ROP to other maternal and neonatal diseases and conditions provides insights into the management of ROP. Suppressing disordered retinal angiogenesis via the modulation of hypoxia-inducible factor, supplementation of insulin-like growth factor (IGF)-1/IGF-binding protein 3 complex, erythropoietin, and its derivatives, polyunsaturated fatty acids, and inhibition of secretogranin III have attracted the attention of researchers. Recently, gut microbiota modulation, non-coding RNAs, and gene therapies have shown promise in regulating ROP. These emerging therapeutics can be used to treat preterm infants with ROP.
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18
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Luo J, Zhao Q, Li Z, Chen L. Multiple roles of apelin/APJ system in eye diseases. Peptides 2022; 152:170767. [PMID: 35181348 DOI: 10.1016/j.peptides.2022.170767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 02/11/2022] [Accepted: 02/12/2022] [Indexed: 10/19/2022]
Abstract
Apelin is an endogenous ligand of G protein-coupled receptor (APJ), and they compose apelin/APJ system. Apelin/APJ system is widely distributed in tissues and plays pleiotropic roles. Attractively, more emphasis has recently been placed on the effects of apelin/APJ system in eye diseases, such as retinopathy of prematurity (ROP), diabetic retinopathy (DR) and diabetic macular edema (DME). In this review, we elaborated the roles of apelin/APJ system in the pathophysiological processes of eye. Concretely, apelin/APJ system induces retinal gliosis and angiogenesis. Hypoxia-inducible factors (HIFs) are involved in apelin/APJ system-triggered ROP progress. Apelin/APJ system mediates DR-induced retinopathy. Apelin/APJ system maintains retinal functions and health by protecting Müller cells from apoptosis. Apelin/APJ system suppresses the NMDA-induced retinal ganglion cell (RGC) loss to protect optic nerve damage. Overall, apelin/APJ system is a potential therapeutic target for eye disease.
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Affiliation(s)
- Jingshun Luo
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of tumor microenvironment responsive drug research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Qun Zhao
- Health Management Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhiyue Li
- Department of Orthopedics, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Linxi Chen
- Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of tumor microenvironment responsive drug research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China.
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19
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Dysregulated genomic and coding-transcriptomic factors in retinopathy of prematurity. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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20
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Taher NO, Ghaddaf AA, Al-Ghamdi SA, Homsi JJ, Al-Harbi BJ, Alomari LK, Almarzouki HS. Intravitreal Anti-vascular Endothelial Growth Factor Injection for Retinopathy of Prematurity: A Systematic Review and Meta-Analysis. Front Med (Lausanne) 2022; 9:884608. [PMID: 35615084 PMCID: PMC9124790 DOI: 10.3389/fmed.2022.884608] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 03/30/2022] [Indexed: 11/18/2022] Open
Abstract
Background Laser photocoagulation and/or intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections constitute the current standard treatment for retinopathy of prematurity (ROP). This systematic review and meta-analysis aimed to assess the efficacy and safety of anti-VEGF monotherapy for ROP treatment using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Methods We searched the Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases. We included randomized controlled trials (RCTs) that compared intravitreal anti-VEGF monotherapy (e.g., bevacizumab, ranibizumab, aflibercept, and pegaptanib) with laser photocoagulation in preterm infants with ROP. We evaluated the rates of recurrence, treatment switching, retreatment, adverse events, and mortality. The risk ratio (RR) was used to represent dichotomous outcomes. Data were pooled using the inverse variance weighting method. The quality of evidence was assessed using the GRADE approach. Risk of bias was assessed using the Revised Cochrane risk of bias tool for randomized trials. Results Seven RCTs (n = 579; 1,158 eyes) were deemed eligible. Three RCTs had an overall low risk of bias, three had some concerns, and one had an overall high risk of bias. The pooled effect estimate showed a statistically significant reduction in adverse events in favor of anti-VEGF monotherapy [RR = 0.17, 95% confidence interval (CI) 0.07–0.44]. The pooled analysis showed no significant difference between the anti-VEGF and laser groups in terms of recurrence rate (RR = 1.56, 95% CI 0.23–10.54), treatment switching (RR = 2.92, 95% CI 0.40–21.05), retreatment (RR = 1.56, 95% CI 0.35–6.96), and mortality rate (RR = 1.28, 95% CI 0.48–3.41). Conclusion Overall, intravitreal anti-VEGF monotherapy was associated with fewer adverse events than laser therapy, rated as high quality of evidence according to the GRADE criteria. Pooled analysis revealed no significant difference between the two arms with respect to the recurrence rate, treatment switching, retreatment, and mortality rate, with quality of evidence ranging from moderate to very low as per the GRADE approach. Systematic Review Registration [https://www.crd.york.ac.uk/prospero/#recordDetails], identifier [CRD42021270077].
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Affiliation(s)
- Nada O. Taher
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
- *Correspondence: Nada O. Taher,
| | - Abdullah A. Ghaddaf
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Sarah A. Al-Ghamdi
- Ophthalmology Saudi Board Program, Jeddah Eye Hospital, Jeddah, Saudi Arabia
| | - Jumanah J. Homsi
- College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Ophthalmology Saudi Board Program, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
| | - Bandar J. Al-Harbi
- Ophthalmology Saudi Board Program, Jeddah Eye Hospital, Jeddah, Saudi Arabia
| | - Lugean K. Alomari
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Hashem S. Almarzouki
- College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
- Department of Ophthalmology, Ministry of the National Guard-Health Affairs, Jeddah, Saudi Arabia
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21
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Retinopathy of prematurity: contribution of inflammatory and genetic factors. Mol Cell Biochem 2022; 477:1739-1763. [PMID: 35262882 DOI: 10.1007/s11010-022-04394-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 02/16/2022] [Indexed: 12/14/2022]
Abstract
Retinopathy of prematurity (ROP) is a retinal vasoproliferative disorder that represents an important cause of childhood visual impairment and blindness. Although oxidative stress has long been implicated in ROP etiology, other prenatal and perinatal factors are also involved. This review focuses on current research involving inflammation and genetic factors in the pathogenesis of ROP. Increasing evidence suggests that perinatal inflammation or infection contributes to ROP pathogenesis. Cytokines and chemokines with a fundamental role in inflammatory responses and that significantly contributing to angiogenesis are analyzed. Microglia cells, the retinal-resident macrophages, are crucial for retinal homeostasis, however, under sustained pathological stimuli release exaggerated amounts of inflammatory mediators and can promote pathological neovascularization. Current modulation of angiogenic cytokines, such as treatment with antibodies to vascular endothelial growth factor (anti-VEGF), has shown efficacy in the treatment of ocular neovascularization; however, some patients are refractory to anti-VEGF agents, suggesting that other angiogenic or anti-angiogenic cytokines need to be identified. Much evidence suggests that genetic factors contribute to the phenotypic variability of ROP. Several studies have implicated the involvement of candidate genes from different signaling pathways in the development of ROP. However, a genetic component with a major impact on ROP has not yet been discovered. Most studies have limitations and did not replicate results. Future research involving bioinformatics, genomics, and proteomics may contribute to finding more genes associated with ROP and may allow discovering better solutions in the management and treatment of ROP.
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22
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Serum vascular endothelial growth factor, insulin-like growth factor-1 and aflibercept levels in retinopathy of prematurity. Jpn J Ophthalmol 2022; 66:151-158. [DOI: 10.1007/s10384-021-00895-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 11/24/2021] [Indexed: 10/19/2022]
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23
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Zhou L, Xu Z, Oh Y, Gamuyao R, Lee G, Xie Y, Cho H, Lee S, Duh EJ. Myeloid cell modulation by a GLP-1 receptor agonist regulates retinal angiogenesis in ischemic retinopathy. JCI Insight 2021; 6:93382. [PMID: 34673570 PMCID: PMC8675187 DOI: 10.1172/jci.insight.93382] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 10/20/2021] [Indexed: 01/04/2023] Open
Abstract
Ischemic retinopathies including diabetic retinopathy are major causes of blindness. Although neurons and Müller glia are recognized as important regulators of reparative and pathologic angiogenesis, the role of mononuclear phagocytes (MPs) — particularly microglia, the resident retinal immune cells — is unclear. Here, we found MP activation in human diabetic retinopathy, especially in neovessels from human neovascular membranes in proliferative retinopathy, including TNF-α expression. There was similar activation in the mouse oxygen-induced retinopathy (OIR) model of ischemia-induced neovascularization. Glucagon-like peptide-1 receptor (GLP-1R) agonists are in clinical use for glycemic control in diabetes and are also known to modulate microglia. Herein, we investigated the effect of a long-acting GLP-1R agonist, NLY01. Following intravitreal administration, NLY01 selectively localized to MPs in retina with OIR. NLY01 modulated MPs but not retinal endothelial cell viability, apoptosis, and tube formation in vitro. In OIR, NLY01 treatment inhibited MP infiltration and activation, including MP expression of cytokines in vivo. NLY01 significantly suppressed global induction of retinal inflammatory cytokines, promoted reparative angiogenesis, and suppressed pathologic retinal neovascularization. Collectively, these findings indicate the important role of mononuclear phagocytes in regulation of retinal vascularization in ischemia and suggest modulation of MPs as a potentially new treatment strategy for ischemic retinopathies.
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Affiliation(s)
| | | | - Yumin Oh
- Wilmer Eye Institute and.,The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | | | | | | | - Seulki Lee
- Wilmer Eye Institute and.,The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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24
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Yang X, Wang J, Chen C. Serum VEGF and Ang-2 Levels in Infants Before and After Laser Treatment for Retinopathy of Prematurity. Fetal Pediatr Pathol 2021; 40:407-413. [PMID: 32075465 DOI: 10.1080/15513815.2020.1721625] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
To investigate VEGF and Ang-2 level changes in the systemic circulation after laser photocoagulation in premature infants with ROP. Methods: Eleven infants (4 girls and 7 boys) had serum levels determined for VEGF and Ang-2, collected 1 day prior to and 7 days after ROP laser therapy. Serum levels of VEGF and Ang-2 were quantified by enzyme-linked immunosorbent assay (ELISA). Results: Serum VEGF levels were significantly lower at 7 days after laser therapy compared to that at 1 day prior to laser therapy (p = 0.045). Serum Ang-2 levels increased significantly at 7 days after laser therapy compared with that at 1 day prior to laser therapy (p = 0.046). Conclusions: Serum VEGF levels in patients with ROP were suppressed and Ang-2 levels elevated significantly after laser therapy. The results suggest that changes in VEGF and Ang-2 serum levels may reflect regression and treatment of ROP.
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Affiliation(s)
- Xiaofeng Yang
- Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China.,Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China.,Department of Neonatology, Children's Hospital of Soochow University, Suzhou, Jiangsu province, China
| | - Junping Wang
- Department of Neonatology, Guangdong Women and Children Hospital, Guangzhou, Guangdong province, China
| | - Chao Chen
- Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China.,Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
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25
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Abcouwer SF, Shanmugam S, Muthusamy A, Lin CM, Kong D, Hager H, Liu X, Antonetti DA. Inflammatory resolution and vascular barrier restoration after retinal ischemia reperfusion injury. J Neuroinflammation 2021; 18:186. [PMID: 34446062 PMCID: PMC8394696 DOI: 10.1186/s12974-021-02237-5] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 08/11/2021] [Indexed: 02/08/2023] Open
Abstract
Background Several retinal pathologies exhibit both inflammation and breakdown of the inner blood-retinal barrier (iBRB) resulting in vascular permeability, suggesting that treatments that trigger resolution of inflammation may also promote iBRB restoration. Methods Using the mouse retinal ischemia-reperfusion (IR) injury model, we followed the time course of neurodegeneration, inflammation, and iBRB disruption and repair to examine the relationship between resolution of inflammation and iBRB restoration and to determine if minocycline, a tetracycline derivative shown to reverse microglial activation, can hasten these processes. Results A 90-min ischemic insult followed by reperfusion in the retina induced cell apoptosis and inner retina thinning that progressed for approximately 2 weeks. IR increased vascular permeability within hours, which resolved between 3 and 4 weeks after injury. Increased vascular permeability coincided with alteration and loss of endothelial cell tight junction (TJ) protein content and disorganization of TJ protein complexes. Shunting of blood flow away from leaky vessels and dropout of leaky capillaries were eliminated as possible mechanisms for restoring the iBRB. Repletion of TJ protein contents occurred within 2 days after injury, long before restoration of the iBRB. In contrast, the eventual re-organization of TJ complexes at the cell border coincided with restoration of the barrier. A robust inflammatory response was evident a 1 day after IR and progressed to resolution over the 4-week time course. The inflammatory response included a rapid and transient infiltration of granulocytes and Ly6C+ classical inflammatory monocytes, a slow accumulation of Ly6Cneg monocyte/macrophages, and activation, proliferation, and mobilization of resident microglia. Extravasation of the majority of CD45+ leukocytes occurred from the superficial plexus. The presence of monocyte/macrophages and increased numbers of microglia were sustained until the iBRB was eventually restored. Intervention with minocycline to reverse microglial activation at 1 week after injury promoted early restoration of the iBRB coinciding with decreased expression of mRNAs for the microglial M1 markers TNF-α, IL-1β, and Ptgs2 (Cox-2) and increased expression of secreted serine protease inhibitor Serpina3n mRNA. Conclusions These results suggest that iBRB restoration occurs as TJ complexes are reorganized and that resolution of inflammation and restoration of the iBRB following retinal IR injury are functionally linked. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-021-02237-5.
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Affiliation(s)
- Steven F Abcouwer
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, 48105, USA.
| | - Sumathi Shanmugam
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, 48105, USA
| | | | - Cheng-Mao Lin
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, 48105, USA
| | - Dejuan Kong
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, 48105, USA
| | - Heather Hager
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, 48105, USA
| | - Xuwen Liu
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, 48105, USA
| | - David A Antonetti
- Department of Ophthalmology and Visual Sciences, Michigan Medicine, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, 48105, USA.,Department of Molecular and Integrative Physiology, Ann Arbor, MI, 48109, USA
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26
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Shu X, Hu Y, Huang C, Wei N. Nimbolide ameliorates the streptozotocin-induced diabetic retinopathy in rats through the inhibition of TLR4/NF-κB signaling pathway. Saudi J Biol Sci 2021; 28:4255-4262. [PMID: 34354407 PMCID: PMC8324995 DOI: 10.1016/j.sjbs.2021.06.039] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/01/2021] [Accepted: 06/13/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) is a common problem in the diabetic patients due to the high blood glucose level. DR affects more number of diabetic patients worldwide with irreversible vision loss. OBJECTIVE The current investigation was focused to reveal the therapeutic actions of nimbolide against the streptozotocin (STZ)-provoked DR in rats through inhibition of TLR4/NF-κB pathway. METHODOLOGY DR was provoked to the rats through administering a single dose of STZ (60 mg/kg) intraperitoneally. The DR rats were then supplemented with the 50 mg/kg of nimbolide for 60 days. The bodyweight and blood glucose level was measured using standard methods. The lipid profiles (cholesterol, TG, LDL, and HDL), inflammatory markers, and antioxidants level was detected using respective kits. The level of MCP-1, VEGF, and MMP-9 was quantified using kits. The morphometric analysis of retinal tissues were done. The mRNA expressions of target genes were studied using RT-PCR assay. RESULTS Nimbolide treatment effective decreased the food intake and blood glucose, and improved the bodyweight of STZ-provoked animals. The levels of pro-inflammatory mediators, cholesterol, TG, LDL, and HDL, MCP-1, VEGF, and MMP-9 was remarkably suppressed by the nimbolide treatment. Nimbolide also improved the antioxidants, retinal thickness and cell numbers. The TLR4/NF-κB pathway was appreciably inhibited by the nimbolide. CONCLUSION Overall, our findings demonstrated that the nimbolide attenuated the STZ-provoked DR in rats through inhibiting the TLR4/NF-κB pathway.
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Affiliation(s)
- Xiangwen Shu
- Second Department of Ophthalmology, Second People's Hospital of Jinan, Jinan 250001, China
| | - Yali Hu
- Department of Ophthalmology, Binzhou Hospital of Traditional Chinese Medicine, Binzhou 256600, China
| | - Chao Huang
- Department of Ophthalmology, The Second People’s Hospital of Jinan, Jinan 250000, China
| | - Ning Wei
- Department of Ophthalmology, The Second People’s Hospital of Jinan, Jinan 250000, China
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27
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Zhou T, Liu Y, Yang Z, Ni B, Zhu X, Huang Z, Xu H, Feng Q, Lin X, He C, Liu X. IL-17 signaling induces iNOS+ microglia activation in retinal vascular diseases. Glia 2021; 69:2644-2657. [PMID: 34288126 DOI: 10.1002/glia.24063] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 07/11/2021] [Accepted: 07/12/2021] [Indexed: 12/18/2022]
Abstract
Activation of microglia and inflammation-mediated vascular damages are suggested to play a decisive role in the pathogenesis of various retinopathies. The inducible nitric oxide synthase (iNOS) was required for activated microglia-mediated injuries. However, the induction mechanism of microglia activation during retinal vascular diseases is still elusive. Here we showed that IL-17 induced microglia activation with high expression of iNOS and promoted the development of retinal vascular diseases. IL-17-dependent activation of the STAT3-iNOS pathway was essentially required for microglia activation, which promoted endothelial cell growth and accelerated vascular leakage and leukostasis via IL-6 in vitro and in vivo. Taken together, our data provide novel mechanistic insights on microglia activation-mediated retinopathy, unveil the specific role of IL-17 on microglia, and define novel therapeutic targets for treating retinal vascular diseases.
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Affiliation(s)
- Tian Zhou
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Yan Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Ziqi Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Biyan Ni
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Xiaowei Zhu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Zijing Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Huiyi Xu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Qiumin Feng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Xiaojing Lin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Chang He
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
| | - Xialin Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, P. R. China
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28
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Cytokine Levels in Human Vitreous in Proliferative Diabetic Retinopathy. Cells 2021; 10:cells10051069. [PMID: 33946446 PMCID: PMC8147162 DOI: 10.3390/cells10051069] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/16/2021] [Accepted: 04/16/2021] [Indexed: 02/05/2023] Open
Abstract
In this study, we compare the vitreous cytokine profile in patients with proliferative diabetic retinopathy (PDR) to that of patients without PDR. The identification of novel cytokines involved in the pathogenesis of PDR provides candidate therapeutic targets that may stand alone or work synergistically with current therapies in the management of diabetic retinopathy. Undiluted vitreous humor specimens were collected from 74 patients undergoing vitrectomy for various vitreoretinal disorders. Quantitative immunoassay was performed for a panel of 36 neuroinflammatory cytokines in each specimen and assessed to identify differences between PDR (n = 35) and non-PDR (n = 39) patients. Levels of interleukin-8 (IL-8), IL-15, IL-16, vascular endothelial growth factor (VEGF), VEGF-D, c-reactive protein (CRP), serum amyloid-A (SAA), and intracellular adhesion molecule-1 (ICAM1) were significantly increased in the vitreous of PDR patients compared to non-PDR patients (p < 0.05). We report novel increases in IL-15 and IL-16, in addition to the expected VEGF, in the human vitreous humor of patients with PDR. Additionally, we confirm the elevation of ICAM-1, VCAM-1, SAA, IL-8 and CRP in the vitreous of patients with PDR, which has previously been described.
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29
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Vinekar A, Nair AP, Sinha S, Vaidya T, Chakrabarty K, Shetty R, Ghosh A, Sethu S. Tear Fluid Angiogenic Factors: Potential Noninvasive Biomarkers for Retinopathy of Prematurity Screening in Preterm Infants. Invest Ophthalmol Vis Sci 2021; 62:2. [PMID: 33646290 PMCID: PMC7938022 DOI: 10.1167/iovs.62.3.2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Purpose To determine the status of proangiogenic factors in the tear fluid of preterm infants with and without retinopathy of prematurity (ROP). Methods Preterm infants (n = 36) undergoing routine ROP screening included in the prospective study were categorized as No-ROP (n = 13, no ROP at any visits), ROP (if ROP was present at first visit; n = 18), or No-ROP to ROP (no disease at first visit, but developed ROP subsequently; n = 5). Infants with ROP were also grouped as progressing (n = 7) and regressing (n = 16) based on ROP evolution between the first and subsequent visits. Schirmer's strips were used to collect tear fluid and proangiogenic factors (VEGF, angiogenin, soluble vascular cell adhesion molecule, and fractalkine) levels (in picograms per milliliter) in tear fluid were measured by multiplex ELISA. Results Lower levels of VEGF (135 ± 69; mean ± standard deviation) and higher levels of angiogenin (6568 ± 4975) were observed in infants with ROP compared with infants without ROP (172.5 ± 54.0; 4139 ± 3909) at the first visit. Significantly lower levels of VEGF were observed in the No-ROP to ROP group compared with the No-ROP and ROP groups. The VEGF and angiogenin levels at the first visit were significantly lower in infants with ROP with progressing disease. Angiogenin levels negatively correlated with birth weight and gestational age in ROP. The area under the curve (AUC) and odds ratio (OR) analysis demonstrated that angiogenin/birth weight (AUC = 0.776; OR, 8.6); angiogenin/gestational age (AUC = 0.706; OR, 7.3) and Angiogenin/VEGF (AUC = 0.806; OR, 14.3) ratios were able to differentiated preterm infants with and without ROP. Conclusions The association between angiogenin and ROP suggests its possible role in ROP. The ratio of angiogenin level with birth weight, gestational age, and/or VEGF could serve as a potential noninvasive screening biomarker for ROP.
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Affiliation(s)
- Anand Vinekar
- Department of Pediatric Retina, Narayana Nethralaya, Bangalore, India
| | - Archana Padmanabhan Nair
- GROW Research Lab, Narayana Nethralaya Foundation, Bangalore, India.,Manipal Academy of Higher Education, Manipal, India
| | - Shivani Sinha
- Department of Pediatric Retina, Narayana Nethralaya, Bangalore, India
| | - Tanuja Vaidya
- GROW Research Lab, Narayana Nethralaya Foundation, Bangalore, India.,Manipal Academy of Higher Education, Manipal, India
| | | | - Rohit Shetty
- Department of Cornea and Refractive Surgery, Narayana Nethralaya, Bangalore, India
| | - Arkasubhra Ghosh
- GROW Research Lab, Narayana Nethralaya Foundation, Bangalore, India.,Singapore Eye Research Institute, Singapore
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A 60% Edible Ethanolic Extract of Ulmus davidiana Inhibits Vascular Endothelial Growth Factor-Induced Angiogenesis. Molecules 2021; 26:molecules26040781. [PMID: 33546250 PMCID: PMC7913375 DOI: 10.3390/molecules26040781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/27/2021] [Accepted: 01/29/2021] [Indexed: 11/17/2022] Open
Abstract
As abnormal angiogenesis is associated with exacerbation of various diseases, precise control over angiogenesis is imperative. Vascular endothelial growth factor (VEGF), the most well-known angiogenic factor, binds to VEGF receptor (VEGFR), activates various signaling pathways, and mediates angiogenesis. Therefore, blocking the VEGF-induced angiogenic response-related signaling pathways may alleviate various disease symptoms through inhibition of angiogenesis. Ulmus davidiana is a safe natural product that has been traditionally consumed, but its effects on endothelial cells (ECs) and the underlying mechanism of action are unclear. In the present study, we focused on the effect of a 60% edible ethanolic extract of U. davidiana (U60E) on angiogenesis. U60E inhibited the VEGF-mediated proliferation, tube formation, and migration ability of ECs. Mechanistically, U60E inhibited endothelial nitric oxide synthase activation and nitric oxide production by blocking the protein kinase B signaling pathway activated by VEGF and consequently inhibiting proliferation, tube formation, and migration of ECs. These results suggest that U60E could be a potential and safe therapeutic agent capable of suppressing proangiogenic diseases by inhibiting VEGF-induced angiogenesis.
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31
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Arima M, Fujii Y, Sonoda KH. Translational Research in Retinopathy of Prematurity: From Bedside to Bench and Back Again. J Clin Med 2021; 10:331. [PMID: 33477419 PMCID: PMC7830975 DOI: 10.3390/jcm10020331] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/09/2021] [Accepted: 01/15/2021] [Indexed: 12/11/2022] Open
Abstract
Retinopathy of prematurity (ROP), a vascular proliferative disease affecting preterm infants, is a leading cause of childhood blindness. Various studies have investigated the pathogenesis of ROP. Clinical experience indicates that oxygen levels are strongly correlated with ROP development, which led to the development of oxygen-induced retinopathy (OIR) as an animal model of ROP. OIR has been used extensively to investigate the molecular mechanisms underlying ROP and to evaluate the efficacy of new drug candidates. Large clinical trials have demonstrated the efficacy of anti-vascular endothelial growth factor (VEGF) agents to treat ROP, and anti-VEGF therapy is presently becoming the first-line treatment worldwide. Anti-VEGF therapy has advantages over conventional treatments, including being minimally invasive with a low risk of refractive error. However, long-term safety concerns and the risk of late recurrence limit this treatment. There is an unmet medical need for novel ROP therapies, which need to be addressed by safe and minimally invasive therapies. The recent progress in biotechnology has contributed greatly to translational research. In this review, we outline how basic ROP research has evolved with clinical experience and the subsequent emergence of new drugs. We discuss previous and ongoing trials and present the candidate molecules expected to become novel targets.
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Affiliation(s)
- Mitsuru Arima
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 8128582, Japan; (Y.F.); (K.-H.S.)
- Center for Clinical and Translational Research, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 8128582, Japan
| | - Yuya Fujii
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 8128582, Japan; (Y.F.); (K.-H.S.)
| | - Koh-Hei Sonoda
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 8128582, Japan; (Y.F.); (K.-H.S.)
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32
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Feng J, Chen L, Jiang Y, Tao Y. The Role of Apelin/APJ in a Mouse Model of Oxygen-induced Retinopathy. Invest Ophthalmol Vis Sci 2021; 61:47. [PMID: 32729912 PMCID: PMC7425705 DOI: 10.1167/iovs.61.8.47] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Purpose The aim of this study was to investigate apelin and its potential neovascularization role in retinopathy of prematurity (ROP) along with the inhibitory effects of its antagonist. Methods We used an oxygen-induced retinopathy (OIR) mouse model to explore the progress of ROP. Apelin and angiotensin receptor-like 1 APJ expressions were examined in the retina using immunohistochemistry, quantitative polymerase chain reaction, and Western blot analysis. Additionally, the retina was examined by whole-mount staining to evaluate the retinal vessel area, vessel density, capillary width, and the number and length of tip cells. The expression of the phosphorylated mTOR (p-mTOR), p-PI3K/Akt, and p-Erk signaling pathway was also evaluated using Western blot analysis. Results Apelin promoted the development of superficial and deep retinal blood vessels, especially for tip cells during the physical development of retinal vessels. Additionally, apelin stimulated the density of the peripheral retinal zone vessels in OIR mice. The apelin and APJ expression levels significantly increased for the OIR model during their hypoxic phase. Next, we found that apelin mRNA levels in the OIR mice peaked at six hours after return to ambient conditions at P12, whereas the APJ mRNA levels peaked later at P17. Furthermore, the expression of p-mTOR, p-Akt, and p-Erk were all up-regulated in OIR mice whereas F13A suppressed them instead. Conclusions Our results suggest that apelin/APJ signaling pathway is a key factor for hypoxia-induced pathologic angiogenesis, which is a very promising new target for the treatment of ROP.
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Ulhaq ZS, Soraya GV, Budu, Wulandari LR. The role of IL-6-174 G/C polymorphism and intraocular IL-6 levels in the pathogenesis of ocular diseases: a systematic review and meta-analysis. Sci Rep 2020; 10:17453. [PMID: 33060644 PMCID: PMC7566646 DOI: 10.1038/s41598-020-74203-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 09/26/2020] [Indexed: 02/08/2023] Open
Abstract
Interleukin-6 (IL-6) is one of the key regulators behind the inflammatory and pathological process associated with ophthalmic diseases. The role of IL-6-174 G/C polymorphism as well as intraocular IL-6 levels among various eye disease patients differ across studies and has not been systematically reviewed. Thus, this study aims to provide a summary to understand the relationship between IL-6 and ophthalmic disease. In total, 8,252 and 11,014 subjects for IL-6-174 G/C and intraocular levels of IL-6, respectively, were retrieved from PubMed, Scopus and Web of Science. No association was found between IL-6-174 G/C polymorphisms with ocular diseases. Subgroup analyses revealed a suggestive association between the GC genotype of IL-6-174 G/C with proliferative diabetic retinopathy (PDR). Further, the level of intraocular IL-6 among ocular disease patients in general was found to be higher than the control group [standardized mean difference (SMD) = 1.41, 95% confidence interval (CI) 1.24-1.58, P < 0.00001]. Closer examination through subgroup analyses yielded similar results in several ocular diseases. This study thus indicates that the IL-6-174 G/C polymorphism does not predispose patients to ocular disease, although the GC genotype is likely to be a genetic biomarker for PDR. Moreover, intraocular IL-6 concentrations are related to the specific manifestations of the ophthalmic diseases. Further studies with larger sample sizes are warranted to confirm this conclusion.
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Affiliation(s)
- Zulvikar Syambani Ulhaq
- Department of Biochemistry, Faculty of Medicine and Health Sciences, Maulana Malik Ibrahim State Islamic University of Malang, Batu, East Java, 65151, Indonesia.
| | - Gita Vita Soraya
- Department of Biochemistry, Faculty of Medicine, Hasanuddin University, Makassar, South Sulawesi, Indonesia
| | - Budu
- Department of Ophthalmology, Faculty of Medicine, Hasanuddin University, Makassar, South Sulawesi, Indonesia
| | - Lely Retno Wulandari
- Department of Ophthalmology, Faculty of Medicine, Brawijaya University, Malang, East Java, Indonesia
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Etanercept as a TNF-alpha inhibitor depresses experimental retinal neovascularization. Graefes Arch Clin Exp Ophthalmol 2020; 259:661-671. [PMID: 33043386 DOI: 10.1007/s00417-020-04956-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 07/07/2020] [Accepted: 10/01/2020] [Indexed: 01/06/2023] Open
Abstract
PURPOSE The formation of retinal neovascularization (RNV) is the primary pathological process underlying retinopathy of prematurity (ROP). Previous studies have shown that inflammatory factors are related to the formation of RNV. Tumor necrosis factor-α (TNF-α), as an important factor in the inflammatory response, is involved in the regulation of RNV formation. However, the mechanism through which TNF-α inhibition reduces RNV formation is not fully clarified. Therefore, the purpose of this study was to explore the effect of etanercept, an inhibitor of TNF-α, on RNV, and its possible mechanism. METHODS In vivo, an oxygen-induced retinopathy (OIR) mouse model was used to determine the effect of etanercept on the formation of RNV by performing immunostaining. The effect of etanercept on tumor necrosis factor receptor-associated factor 2 (TRAF2), pro-angiogenic-related factors, and pro/anti-inflammatory factors in OIR mice was assessed by real-time PCR and Western blotting. In vitro, the effect of etanercept on TNF-α-induced human retinal microvascular endothelial cell tube formation was evaluated by tube formation assays, and the potential mechanism of etanercept was explored by Western blotting. RESULTS In vivo, etanercept reduced the area of RNV and decreased the expression of TRAF2 in the OIR mouse model. Etanercept also suppressed the expression of several pro-angiogenic factors and regulated the pro/anti-inflammatory factors. In vitro, etanercept reduced endothelial cell tube formation by inhibiting activation of the NF-κB signaling pathway. CONCLUSION Etanercept can regulate pro/anti-inflammatory factors and reduce the expression of pro-angiogenic factors by inhibiting NF-κB phosphorylation, thereby reducing RNV formation.
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Legocki AT, Zepeda EM, Gillette TB, Grant LE, Shariff A, Touch P, Lee AY, Ding L, Estrada MM, Tarczy-Hornoch K, Lee CS, Mayock DE, Pepple KL, Cabrera MT. Vitreous Findings by Handheld Spectral-Domain OCT Correlate with Retinopathy of Prematurity Severity. Ophthalmol Retina 2020; 4:1008-1015. [PMID: 32446843 PMCID: PMC7541565 DOI: 10.1016/j.oret.2020.03.027] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 03/25/2020] [Accepted: 03/26/2020] [Indexed: 11/24/2022]
Abstract
PURPOSE To evaluate the association between retinopathy of prematurity (ROP) and vitreous findings in premature infants detected by handheld spectral-domain (SD) OCT. DESIGN Prospective, observational cohort study. PARTICIPANTS Consecutive sample of 92 premature infants requiring ROP screening at 2 academic neonatal intensive care units between July 2015 and March 2018. METHODS Infants underwent handheld SD OCT at the time of routine ROP examinations. Two masked, trained graders analyzed right-eye vitreoretinal findings, including semiautomated quantification of punctate hyperreflective vitreous opacities within 5 foveal or parafoveal B-scans (vitreous opacity ratio). MAIN OUTCOME MEASURES Excluding posttreatment data, vitreous findings were compared with clinical ROP diagnoses. RESULTS Agreement between image graders for all vitreoretinal findings was 91% (κ = 0.86; 95% confidence interval, 0.82-0.90; P < 0.001). Among 92 infants undergoing 280 imaging sessions (52% male; mean gestational age, 28.3 ± 2.8 weeks; mean birthweight, 1014.5 ± 285.0 g), 36 of 92 (39%) demonstrated ROP. Punctate hyperreflective vitreous opacities were identified in 61 of 92 infants (66%). The presence of punctate hyperreflective vitreous opacities at least once was associated with a diagnosis of ROP (62% vs. 29% without opacities; P = 0.003), maximum ROP stage (P = 0.001), preplus or plus disease (24% vs. 5%; P = 0.005), and type 1 disease (14% vs. 2%; P = 0.03). Among 29 infants (45 imaging sessions) with right-eye punctate hyperreflective vitreous opacities, the vitreous opacity ratio from 2 graders (F1 score, 0.82 ± 0.36; Dice coefficient, 0.97 ± 0.04) correlated with ROP stage (P = 0.02). Tractional vitreous bands on imaging correlated with plus disease status (29% vs. 5% without bands; P = 0.05). CONCLUSIONS Punctate hyperreflective vitreous opacities and tractional vitreous bands predict the presence and severity of ROP. Further studies should explore handheld OCT as a noninvasive ROP screening tool.
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Affiliation(s)
- Alex T Legocki
- Department of Ophthalmology, University of Washington, Seattle, Washington
| | - Emily M Zepeda
- Department of Ophthalmology, University of Washington, Seattle, Washington
| | - Thomas B Gillette
- Department of Ophthalmology, University of Washington, Seattle, Washington
| | - Laura E Grant
- Department of Ophthalmology, University of Washington, Seattle, Washington
| | - Ayesha Shariff
- Department of Ophthalmology, University of Washington, Seattle, Washington
| | - Phanith Touch
- Department of Ophthalmology, University of Washington, Seattle, Washington
| | - Aaron Y Lee
- Department of Ophthalmology, University of Washington, Seattle, Washington
| | - Leona Ding
- Department of Ophthalmology, University of Washington, Seattle, Washington
| | - Marcela M Estrada
- Department of Ophthalmology, University of Washington, Seattle, Washington
| | - Kristina Tarczy-Hornoch
- Department of Ophthalmology, University of Washington, Seattle, Washington; Department of Ophthalmology, Seattle Children's Hospital, Seattle, Washington
| | - Cecilia S Lee
- Department of Ophthalmology, University of Washington, Seattle, Washington
| | - Dennis E Mayock
- Department of Pediatrics, University of Washington, Seattle, Washington; Department of Pediatrics, Seattle Children's Hospital, Seattle, Washington
| | - Kathryn L Pepple
- Department of Ophthalmology, University of Washington, Seattle, Washington
| | - Michelle T Cabrera
- Department of Ophthalmology, University of Washington, Seattle, Washington; Department of Ophthalmology, Seattle Children's Hospital, Seattle, Washington.
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Jo DH, Kim JH. Toward the Clinical Application of Therapeutic Angiogenesis Against Pediatric Ischemic Retinopathy. J Lipid Atheroscler 2020; 9:268-282. [PMID: 32821736 PMCID: PMC7379088 DOI: 10.12997/jla.2020.9.2.268] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 04/29/2020] [Accepted: 05/13/2020] [Indexed: 11/13/2022] Open
Abstract
Therapeutic angiogenesis refers to strategies of inducing angiogenesis to treat diseases involving ischemic conditions. Historically, most attempts and achievements have been related to coronary and peripheral artery diseases. In this review, we propose the clinical application of therapeutic angiogenesis for the treatment of pediatric ischemic retinopathy, including retinopathy of prematurity, familial exudative retinopathy, and NDP-related retinopathy. These diseases are all characterized by the reduction of physiological angiogenesis and the following induction of pathological angiogenesis. Therapeutic angiogenesis, which supplements insufficient physiological angiogenesis, may be a therapeutic approach for ischemic conditions. Various molecules and modalities can be utilized to apply therapeutic angiogenesis for the treatment of ischemic retinopathy, as in coronary and peripheral artery diseases. Experiences with cardiovascular diseases provide a useful reference for the further clinical application of therapeutic angiogenesis in pediatric ischemic retinopathy. Recombinant proteins and gene therapy are powerful tools to deliver angiogenic factors to retinal tissues directly. Furthermore, endothelial progenitor or bone marrow-derived cells can be injected into the vitreous cavity of the eye for therapeutic angiogenesis. Intraocular injections are highly promising for the delivery of therapeutics for therapeutic angiogenesis. We expect that therapeutic angiogenesis will be a breakthrough in the treatment of pediatric ischemic retinopathy.
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Affiliation(s)
- Dong Hyun Jo
- Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Hun Kim
- Fight against Angiogenesis-Related Blindness, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.,Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.,Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea
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Jiang B, Geng Q, Li T, Mohammad Firdous S, Zhou X. Morin attenuates STZ-induced diabetic retinopathy in experimental animals. Saudi J Biol Sci 2020; 27:2139-2142. [PMID: 32714041 PMCID: PMC7376113 DOI: 10.1016/j.sjbs.2020.06.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 05/21/2020] [Accepted: 06/01/2020] [Indexed: 01/14/2023] Open
Abstract
Diabetic retinopathy (DR) occurs in untreated diabetic patients due to the strong influence of oxidative stress. Bioflavonoids are well known for their antioxidant property. Morin, a bioflavonoid, has been demonstrated for its antioxidant as well as antidiabetic activity. Thus, this research work intended to determine the ameliorative impact of morin in DR rats using STZ-induced type 1 diabetic model. To induce type 1 diabetic in rats STZ (60 mg/kg) was administered intraperitoneally. Grouping of animals was done as described below (n = 6), where, group I - normal control, group II - diabetic control, group III - morin (25 mg/kg), group IV - morin (50 mg/kg), and group V - metformin (350 mg/kg) were used. All the animals underwent treatment for 60 days as given above. It was observed that supplementation of morin (25 and 50 mg/kg) showed a noteworthy decline in elevated serum glucose level. Moreover, decrease in the level of LPO and improved activity of endogenous antioxidants (GPx, CAT, and SOD) was observed in morin treated groups. It also notably drops the concentration of TNF-α, IL-1β, and VEGF in the tissue homogenate of the retina. Furthermore, it increased the retinal thickness and cell count in the ganglion cell layer of the retina in diabetic animals. Hence, we can conclude that morin encumbers the progression of DR in diabetic animals, which may be via antioxidant property and suppression of TNF-α, IL-1β, and VEGF.
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Key Words
- AGEs, Advanced glycated end products
- Antioxidants
- BGL, Blood glucose level
- BRB, Blood retinal barrier
- CAT, Catalase
- DAG, Diacylglycerol
- Diabetic retinopathy
- GPx, Glutathione peroxidase
- IL-1β and VEGF
- IL-1β, Interleukin 1 beta
- LPO, Lipid peroxidase
- Morin
- PKC, Protein kinase C
- ROS, Reactive oxygen species
- SOD, Superoxide dismutase
- STZ, Streptozotocin
- TNF-α
- TNF-α, Tumor necrosis factor alpha
- VEGF, Vascular endothelial growth factor
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Affiliation(s)
- Bo Jiang
- Department of Ophthalmology, Jinshan Hospital of Fudan University, Jinshan District, Shanghai 201508, China
| | - Qingsen Geng
- Department of Eye Fundus,Liaocheng Guangming Ophthalmological Hospital, Liaocheng, Shandong 252000, China
| | - Tao Li
- Department of Ophthalmology, Jinshan Hospital of Fudan University, Jinshan District, Shanghai 201508, China
| | - Sayeed Mohammad Firdous
- Department of Pharmacology, Calcutta Institute of Pharmaceutical Technology & AHS, Uluberia, Howrah 711316, West Bengal, India
| | - Xiaodong Zhou
- Department of Ophthalmology, Jinshan Hospital of Fudan University, Jinshan District, Shanghai 201508, China
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Cheng Y, Zhu X, Linghu D, Xu Y, Liang J. Serum levels of cytokines in infants treated with conbercept for retinopathy of prematurity. Sci Rep 2020; 10:12695. [PMID: 32728160 PMCID: PMC7391743 DOI: 10.1038/s41598-020-69684-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 07/06/2020] [Indexed: 01/28/2023] Open
Abstract
Intravitreal anti-vascular endothelial growth factor (VEGF) agents have revolutionized the treatment of retinopathy of prematurity (ROP); however, there are concerns regarding the potential systemic complications caused by those treatments. This study aimed to determine the serum concentrations of cytokines in infants with ROP and to evaluate the changes in serum VEGF concentrations after intravitreal conbercept (IVC). Sixty infants with ROP treated with IVC 0.25 mg were included. Blood samples were collected before treatment as well as 1 week and 4 weeks after treatment. Serum levels of 45 types of cytokines were measured by a multiplex bead assay. We observed that IVC 0.25 mg in ROP patients suppressed the circulating levels of VEGF-A and VEGF-D as of 1 week after injection, and these growth factor levels returned to baseline at 4 weeks. No significant differences were observed in the serum levels of the other cytokines between baseline and 1 or 4 weeks after IVC.
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Affiliation(s)
- Yong Cheng
- Department of Ophthalmology and Clinical Centre of Optometry, Peking University People's Hospital, Eye Diseases and Optometry Institute, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, College of Optometry, Peking University Health Science Center, 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Xuemei Zhu
- Department of Ophthalmology and Clinical Centre of Optometry, Peking University People's Hospital, Eye Diseases and Optometry Institute, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, College of Optometry, Peking University Health Science Center, 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Dandan Linghu
- Department of Ophthalmology and Clinical Centre of Optometry, Peking University People's Hospital, Eye Diseases and Optometry Institute, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, College of Optometry, Peking University Health Science Center, 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Yongsheng Xu
- Department of Ophthalmology and Clinical Centre of Optometry, Peking University People's Hospital, Eye Diseases and Optometry Institute, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, College of Optometry, Peking University Health Science Center, 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.,Clinical Stem Cell Research Center, Peking University Third Hospital, 49 Huayuan North Road, Haidian District, Beijing, China
| | - Jianhong Liang
- Department of Ophthalmology and Clinical Centre of Optometry, Peking University People's Hospital, Eye Diseases and Optometry Institute, Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases, College of Optometry, Peking University Health Science Center, 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
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Takeda A, Yanai R, Murakami Y, Arima M, Sonoda KH. New Insights Into Immunological Therapy for Retinal Disorders. Front Immunol 2020; 11:1431. [PMID: 32719682 PMCID: PMC7348236 DOI: 10.3389/fimmu.2020.01431] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/03/2020] [Indexed: 12/24/2022] Open
Abstract
In the twentieth century, a conspicuous lack of effective treatment strategies existed for managing several retinal disorders, including age-related macular degeneration; diabetic retinopathy (DR); retinopathy of prematurity (ROP); retinitis pigmentosa (RP); uveitis, including Behçet's disease; and vitreoretinal lymphoma (VRL). However, in the first decade of this century, advances in biomedicine have provided new treatment strategies in the field of ophthalmology, particularly biologics that target vascular endothelial growth factor or tumor necrosis factor (TNF)-α. Furthermore, clinical trials on gene therapy specifically for patients with autosomal recessive or X-linked RP have commenced. The overall survival rates of patients with VRL have improved, owing to earlier diagnoses and better treatment strategies. However, some unresolved problems remain such as primary or secondary non-response to biologics or chemotherapy, and the lack of adequate strategies for treating most RP patients. In this review, we provide an overview of the immunological mechanisms of the eye under normal conditions and in several retinal disorders, including uveitis, DR, ROP, RP, and VRL. In addition, we discuss recent studies that describe the inflammatory responses that occur during the course of these retinal disorders to provide new insights into their diagnosis and treatment.
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Affiliation(s)
- Atsunobu Takeda
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Ophthalmology, Clinical Research Institute, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan
| | - Ryoji Yanai
- Department of Ophthalmology, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan
| | - Yusuke Murakami
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Mitsuru Arima
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koh-Hei Sonoda
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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40
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Delia Nicoară S. Therapeutic Options in Retinopathy of Prematurity. NEONATAL MEDICINE 2019. [DOI: 10.5772/intechopen.80956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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A Surgical Technique for the Management of Tractional Retinal Detachment in Aggressive Posterior Retinopathy of Prematurity Treated With Intravitreal Bevacizumab. Retina 2019; 39 Suppl 1:S156-S159. [DOI: 10.1097/iae.0000000000002304] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Tayman C, Çakır U, Özdemir Ö. Prematür retinopatisinin tanısı ve lazer tedavisine cevabın takibinde VEGF ve IGF-1’in değeri. CUKUROVA MEDICAL JOURNAL 2019. [DOI: 10.17826/cumj.472840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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Wooff Y, Man SM, Aggio-Bruce R, Natoli R, Fernando N. IL-1 Family Members Mediate Cell Death, Inflammation and Angiogenesis in Retinal Degenerative Diseases. Front Immunol 2019; 10:1618. [PMID: 31379825 PMCID: PMC6646526 DOI: 10.3389/fimmu.2019.01618] [Citation(s) in RCA: 170] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 06/28/2019] [Indexed: 12/22/2022] Open
Abstract
Inflammation underpins and contributes to the pathogenesis of many retinal degenerative diseases. The recruitment and activation of both resident microglia and recruited macrophages, as well as the production of cytokines, are key contributing factors for progressive cell death in these diseases. In particular, the interleukin 1 (IL-1) family consisting of both pro- and anti-inflammatory cytokines has been shown to be pivotal in the mediation of innate immunity and contribute directly to a number of retinal degenerations, including Age-Related Macular Degeneration (AMD), diabetic retinopathy, retinitis pigmentosa, glaucoma, and retinopathy of prematurity (ROP). In this review, we will discuss the role of IL-1 family members and inflammasome signaling in retinal degenerative diseases, piecing together their contribution to retinal disease pathology, and identifying areas of research expansion required to further elucidate their function in the retina.
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Affiliation(s)
- Yvette Wooff
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,ANU Medical School, The Australian National University, Canberra, ACT, Australia
| | - Si Ming Man
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Riemke Aggio-Bruce
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Riccardo Natoli
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,ANU Medical School, The Australian National University, Canberra, ACT, Australia
| | - Nilisha Fernando
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
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Li Y, Zhou Y. Interleukin-17: The Role for Pathological Angiogenesis in Ocular Neovascular Diseases. TOHOKU J EXP MED 2019; 247:87-98. [PMID: 30773517 DOI: 10.1620/tjem.247.87] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Ocular neovascular diseases are featured by abnormal angiogenesis in the eye, and they seriously threaten the human visual health. These diseases include proliferative diabetic retinopathy (PDR), age-related macular degeneration (AMD), retinopathy of prematurity (ROP), and retinal vein occlusion (RVO). In fact, ocular neovascular diseases represent the leading causes of vision impairment and blindness worldwide. Ocular neovascularization, the process of pathological vessel formation in eye, underlies ocular neovascular diseases. Cytokines have important regulatory roles in neovascularization through immunological networks. Interleukin (IL)-17, the signature cytokine produced by T helper 17 (Th17) cells, has proven to be involved in ocular neovascularization. However, roles of IL-17 in ocular neovascular diseases still remain controversial. This review provides an overview of the functional roles of IL-17 in ocular neovascular diseases from basic research to clinical evidence by focusing on PDR, AMD, ROP, and RVO. The possible roles of IL-17 in neovascularization are achieved through a regulatory network of cytoskeleton remodeling, vascular endothelial growth factor (VEGF), VEGF-related cytokines, and complement components. Current applications as well as potential therapies targeting IL-17 with genome editing systems are also outlined and discussed. Targeting IL-17 might be a promising therapeutic strategy against ocular neovascular diseases.
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Affiliation(s)
- Yuanjun Li
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University.,Department of Ophthalmology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital
| | - Yedi Zhou
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University.,Hunan Clinical Research Center of Ophthalmic Disease
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de Gaetano M, McEvoy C, Andrews D, Cacace A, Hunter J, Brennan E, Godson C. Specialized Pro-resolving Lipid Mediators: Modulation of Diabetes-Associated Cardio-, Reno-, and Retino-Vascular Complications. Front Pharmacol 2018; 9:1488. [PMID: 30618774 PMCID: PMC6305798 DOI: 10.3389/fphar.2018.01488] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 12/05/2018] [Indexed: 12/18/2022] Open
Abstract
Diabetes and its associated chronic complications present a healthcare challenge on a global scale. Despite improvements in the management of chronic complications of the micro-/macro-vasculature, their growing prevalence and incidence highlights the scale of the problem. It is currently estimated that diabetes affects 425 million people globally and it is anticipated that this figure will rise by 2025 to 700 million people. The vascular complications of diabetes including diabetes-associated atherosclerosis and kidney disease present a particular challenge. Diabetes is the leading cause of end stage renal disease, reflecting fibrosis leading to organ failure. Moreover, diabetes associated states of inflammation, neo-vascularization, apoptosis and hypercoagulability contribute to also exacerbate atherosclerosis, from the metabolic syndrome to advanced disease, plaque rupture and coronary thrombosis. Current therapeutic interventions focus on regulating blood glucose, glomerular and peripheral hypertension and can at best slow the progression of diabetes complications. Recently advanced knowledge of the pathogenesis underlying diabetes and associated complications revealed common mechanisms, including the inflammatory response, insulin resistance and hyperglycemia. The major role that inflammation plays in many chronic diseases has led to the development of new strategies aiming to promote the restoration of homeostasis through the "resolution of inflammation." These strategies aim to mimic the spontaneous activities of the 'specialized pro-resolving mediators' (SPMs), including endogenous molecules and their synthetic mimetics. This review aims to discuss the effect of SPMs [with particular attention to lipoxins (LXs) and resolvins (Rvs)] on inflammatory responses in a series of experimental models, as well as evidence from human studies, in the context of cardio- and reno-vascular diabetic complications, with a brief mention to diabetic retinopathy (DR). These data collectively support the hypothesis that endogenously generated SPMs or synthetic mimetics of their activities may represent lead molecules in a new discipline, namely the 'resolution pharmacology,' offering hope for new therapeutic strategies to prevent and treat, specifically, diabetes-associated atherosclerosis, nephropathy and retinopathy.
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Affiliation(s)
- Monica de Gaetano
- UCD Diabetes Complications Research Centre, Conway Institute and UCD School of Medicine, University College Dublin, Dublin, Ireland
| | - Caitriona McEvoy
- UCD Diabetes Complications Research Centre, Conway Institute and UCD School of Medicine, University College Dublin, Dublin, Ireland
- Renal Transplant Program, University Health Network, Toronto, ON, Canada
| | - Darrell Andrews
- UCD Diabetes Complications Research Centre, Conway Institute and UCD School of Medicine, University College Dublin, Dublin, Ireland
| | - Antonino Cacace
- UCD Diabetes Complications Research Centre, Conway Institute and UCD School of Medicine, University College Dublin, Dublin, Ireland
| | - Jonathan Hunter
- UCD Diabetes Complications Research Centre, Conway Institute and UCD School of Medicine, University College Dublin, Dublin, Ireland
| | - Eoin Brennan
- UCD Diabetes Complications Research Centre, Conway Institute and UCD School of Medicine, University College Dublin, Dublin, Ireland
| | - Catherine Godson
- UCD Diabetes Complications Research Centre, Conway Institute and UCD School of Medicine, University College Dublin, Dublin, Ireland
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46
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Torabi H, Jadidi K, Naderi M. Lamellar macular hole formation following intravitreal bevacizumab injection for choroidal neovascularization by age-related macular degeneration. Oman J Ophthalmol 2018; 11:277-279. [PMID: 30505124 PMCID: PMC6219339 DOI: 10.4103/ojo.ojo_33_2017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
This report describes a lamellar macular hole formation subsequent to intravitreal bevacizumab injection for the treatment of choroidal neovascularization (CNV) by age-related macular degeneration. A 67-year-old woman with bilateral CNV underwent 3 monthly intravitreal bevacizumab injections in her both eyes. One month after the third bilateral injection, vision loss happened. Optical coherence tomography performed for further evaluation that showed reduction of intra- and sub-retinal fluid associated with lamellar macular hole development in both eyes. Although macular hole formation, especially bilateral form, is a rare complication of intravitreal injections, surgeons should consider macular hole development in cases with vision deterioration following intravitreal bevacizumab injection.
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Affiliation(s)
- Hamidreza Torabi
- Health Management Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Khosrow Jadidi
- Health Management Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mostafa Naderi
- Health Management Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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PROGRESSIVE RETINAL DETACHMENT IN INFANTS WITH RETINOPATHY OF PREMATURITY TREATED WITH INTRAVITREAL BEVACIZUMAB OR RANIBIZUMAB. Retina 2018; 38:1079-1083. [PMID: 28471890 DOI: 10.1097/iae.0000000000001685] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
PURPOSE Fibrovascular contraction and tractional retinal detachment (TRD) are recognized complications associated with the use of anti-vascular endothelial growth factor agents in vasoproliferative vitreoretinopathies. The authors characterize TRDs that developed after intravitreal bevacizumab or ranibizumab therapy for vascularly active retinopathy of prematurity. METHODS This is an international, multicenter, interventional, retrospective, case series. Thirty-five eyes from 23 infants were included. Inclusion required anti-vascular endothelial growth factor treatment of Type 1 retinopathy of prematurity with progression to TRD. RESULTS Mean gestational age was 26 ± 2 weeks, and mean birth weight was 873 ± 341 g. Mean postmenstrual age on the day of injection was 35 ± 2 weeks. Retinal detachment was noted a mean of 70 days (median, 34; range, 4-335) after injection. Eleven percent detached within 1 week, 23% within 2 weeks, and 49% within 4 weeks. The highest stage of retinopathy of prematurity noted was 4A in 29%, 4B in 37%, and 5 in 34% of eyes. Time to RD negatively correlated with postmenstrual age at the time of injection (Rho = -0.54; P < 0.01). Three TRD configurations were observed: 1) conventional peripheral elevated ridge or volcano-shaped Stage 5 detachment, 2) midperipheral detachment with tight circumferential vectors, and 3) very posterior detachment with prepapillary contraction. Full or partial reattachment was achieved with surgical intervention in 86% of eyes. CONCLUSION Progressive atypical TRD may occur after anti-vascular endothelial growth factor injections for retinopathy of prematurity. The configuration of the detachment varies with the extent of primary retinal vascularization present at the time of treatment.
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Lyu J, Zhang Q, Jin H, Xu Y, Chen C, Ji X, Zhang X, Rao Y, Zhao P. Aqueous cytokine levels associated with severity of type 1 retinopathy of prematurity and treatment response to ranibizumab. Graefes Arch Clin Exp Ophthalmol 2018; 256:1469-1477. [PMID: 29948178 DOI: 10.1007/s00417-018-4034-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 04/05/2018] [Accepted: 06/02/2018] [Indexed: 12/11/2022] Open
Abstract
PURPOSE To determine the aqueous humor levels of cytokines in eyes with type 1 retinopathy of prematurity (ROP) before primary intravitreal injection of ranibizumab (IVR). METHODS Forty-nine infants with type 1 ROP (56 eyes of 28 infants in the threshold ROP group and 42 eyes of 21 infants in the type 1 pre-threshold ROP group) received primary IVR and 49 aqueous humor samples were obtained preoperatively. Aqueous humor samples from 15 infants (15 eyes) undergoing congenital cataract surgery were used as controls. The concentrations of 27 cytokines were measured by a multiplex bead assay. Infants with persistent, recurrent, or progressive ROP after IVR were retreated. RESULTS The preoperative aqueous levels of 16 cytokines were significantly different among type 1 pre-threshold, threshold ROP, and control groups (P < 0.05). The concentrations of vascular endothelial growth factor (VEGF) (P < 0.001), interferon-γ (P < 0.001), interleukin (IL)-10 (P < 0.001), and IL-12 (P < 0.001) were the highest in the threshold ROP group, less in the type 1 pre-threshold ROP group, and the lowest in the control group. Retreatment was given to 55% of infants with ROP within a 48-week follow-up period after primary IVR. Higher VEGF (hazard ratio [HR] = 1.001, P = 0.001) and macrophage inflammatory protein-1β (HR = 1.085, P = 0.022) levels were independently correlated with ROP retreatment. CONCLUSIONS Higher aqueous levels of VEGF and inflammatory cytokines were associated with more severe type 1 ROP and ROP retreatment after primary IVR.
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Affiliation(s)
- Jiao Lyu
- Department of Ophthalmology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong Jiang Road, Shanghai, 200092, China
| | - Qi Zhang
- Department of Ophthalmology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong Jiang Road, Shanghai, 200092, China
| | - Haiying Jin
- Department of Ophthalmology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong Jiang Road, Shanghai, 200092, China
| | - Yu Xu
- Department of Ophthalmology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong Jiang Road, Shanghai, 200092, China
| | - Chunli Chen
- Department of Ophthalmology, Shengli Oilfield Central Hospital, Dongying, Shan Dong Province, China
| | - Xunda Ji
- Department of Ophthalmology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong Jiang Road, Shanghai, 200092, China
| | - Xiang Zhang
- Department of Ophthalmology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong Jiang Road, Shanghai, 200092, China
| | - Yuqing Rao
- Department of Ophthalmology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong Jiang Road, Shanghai, 200092, China
| | - Peiquan Zhao
- Department of Ophthalmology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kong Jiang Road, Shanghai, 200092, China.
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Karkhaneh R, Torabi H, Khodabande A, Roohipoor R, Riazi-Esfahani M. Efficacy of Intravitreal Bevacizumab for the Treatment of Zone I Type 1 Retinopathy of Prematurity. J Ophthalmic Vis Res 2018; 13:29-33. [PMID: 29403586 PMCID: PMC5782452 DOI: 10.4103/jovr.jovr_198_16] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Purpose To describe the efficacy of intravitreal bevacizumab for the treatment of type 1 retinopathy of prematurity (ROP) in zone I. Methods Preterm infants with type 1 ROP in zone I (zone I ROP, any stage with plus disease or zone I ROP, stage 3 without plus disease) were enrolled in this prospective study. Intravitreal bevacizumab (0.625 mg/0.025 ml) was injected under topical anesthesia. Patients were followed weekly for 4 weeks and then biweekly till 90 weeks gestational age. Results Seventy eyes of 35 patients with type 1 ROP in zone I were enrolled. At a gestational age of 90 weeks, ROP regressed with complete or near-complete peripheral retinal vascularization, in 82.9% of eyes after a single injection and in 92.9% of eyes after up to two injections. In five eyes (7.1%), ROP progressed to stage 4B or 5, so surgical management was required. There were no major complications such as endophthalmitis, cataract, or vitreous hemorrhage after injection. Conclusion Intravitreal bevacizumab injection is an effective method for the management of patients with Zone I ROP requiring treatment; however, some cases may progress to more advanced stages and require surgical management. Close monitoring for recurrence or progression is necessary. Eyes with persistent zone I ROP may progress to advanced stages when treated with intravitreal bevacizumab injection and re-treatment may be needed.
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Affiliation(s)
- Reza Karkhaneh
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Department of Ophthalmology, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamidreza Torabi
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Department of Ophthalmology, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Alireza Khodabande
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Department of Ophthalmology, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramak Roohipoor
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Department of Ophthalmology, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Riazi-Esfahani
- Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.,Department of Ophthalmology, Tehran University of Medical Sciences, Tehran, Iran
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Holm M, Morken TS, Fichorova RN, VanderVeen DK, Allred EN, Dammann O, Leviton A. Systemic Inflammation-Associated Proteins and Retinopathy of Prematurity in Infants Born Before the 28th Week of Gestation. Invest Ophthalmol Vis Sci 2017; 58:6419-6428. [PMID: 29260199 PMCID: PMC5736326 DOI: 10.1167/iovs.17-21931] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Purpose To assess the association between systemic levels of inflammation-associated proteins and severe retinopathy of prematurity (ROP) in extremely preterm infants. Methods We collected whole blood on filter paper on postnatal days 1, 7, 14, 21, and 28 from 1205 infants born before the 28th week of gestation, and measured the concentrations of 27 inflammation-associated, angiogenic, and neurotrophic proteins. We calculated odds ratios with 95% confidence intervals for the association between top quartile concentrations of each protein and prethreshold ROP. Results During the first three weeks after birth, high concentrations of VEGF-R1, myeloperoxidase (MPO), IL-8, intercellular adhesion molecule (ICAM)-1, matrix metalloproteinase 9, erythropoietin, TNF-α, and basic fibroblast growth factor were associated with an increased risk for prethreshold ROP. On day 28, high levels of serum amyloid A, MPO, IL-6, TNF-α, TNF-R1/-R2, IL-8, and ICAM-1 were associated with an increased risk. Top quartile concentrations of the proinflammatory cytokines TNF-α and IL-6 were associated with increased risks of ROP when levels of neuroprotective proteins and growth factors, including BDNF, insulin-like growth factor 1, IGFBP-1, VEGFR-1 and -2, ANG-1 and PlGF, were not in the top quartile. In contrast, high concentrations of NT-4 and BDNF appeared protective only in infants without elevated inflammatory mediators. Conclusions Systemic inflammation during the first postnatal month was associated with an increased risk of prethreshold ROP. Elevated concentrations of growth factors, angiogenic proteins, and neurotrophins appeared to modulate this risk, and were capable of reducing the risk even in the absence of systemic inflammation.
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Affiliation(s)
- Mari Holm
- Department of Clinical and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Pediatrics, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Tora S Morken
- Department of Neuromedicine and Movement Science (INB), Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Ophthalmology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Raina N Fichorova
- Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | - Deborah K VanderVeen
- Department of Ophthalmology, Children's Hospital Boston, Boston, Massachusetts, United States.,Department of Ophthalmology, Harvard Medical School, Harvard University, Boston, Massachusetts, United States
| | - Elizabeth N Allred
- Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States.,Department of Neurology, Harvard Medical School, Harvard University, Boston, Massachusetts, United States
| | - Olaf Dammann
- Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, Massachusetts, United States.,Perinatal Epidemiology Unit, Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany
| | - Alan Leviton
- Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States.,Department of Neurology, Harvard Medical School, Harvard University, Boston, Massachusetts, United States
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