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      Hyperoxia-Induced Proliferative Retinopathy: Early Interruption of Retinal Vascular Development with Severe and Irreversible Neurovascular Disruption

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          Abstract

          Bronchopulmonary dysplasia (BPD) is a major cause of neonatal morbidity in premature infants, occurring as a result of arrested lung development combined with multiple postnatal insults. Infants with BPD exposed to supplemental oxygen are at risk of retinopathy of prematurity as well. Thus, we studied the effects of hyperoxia on the retinal vasculature in a murine model of BPD. The retinal phenotype of this model, which we termed hyperoxia-induced proliferative retinopathy (HIPR), shows severe disruption of retinal vasculature and loss of vascular patterning, disorganized intra-retinal angiogenesis, inflammation and retinal detachment. Neonatal mice were subjected to 75% oxygen exposure from postnatal day (P)0 to P14 to model BPD, then allowed to recover in room air for 1 (P15), 7 (P21), or 14 days (P28). We quantified retinal thickness, protein levels of HIF-1α, NOX2, and VEGF, and examined the cellular locations of these proteins by immunohistochemistry. We examined the retinal blood vessel integrity and inflammatory markers, including macrophages (F4/80) and lymphocytes (CD45R). Compared to controls, normal retinal vascular development was severely disrupted and replaced by a disorganized sheet of intra-retinal angiogenesis in the HIPR mice. At all time-points, HIPR showed persistent hyaloidal vasculature and a significantly thinner central retina compared to controls. HIF-1α protein levels were increased at P15, while VEGF levels continued to increase until P21. Intra-retinal fibrinogen was observed at P21 followed by sub-retinal deposition in at P28. Inflammatory lymphocytes and macrophages were observed at P21 and P28, respectively. This model presents a severe phenotype of disrupted retinal vascular development, intra-retinal angiogenesis inflammation and retinal detachment.

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          Endogenous VEGF Is Required for Visual Function: Evidence for a Survival Role on Müller Cells and Photoreceptors

          Background Vascular endothelial growth factor (VEGF) is well known for its role in normal and pathologic neovascularization. However, a growing body of evidence indicates that VEGF also acts on non-vascular cells, both developmentally as well as in the adult. In light of the widespread use of systemic and intraocular anti-VEGF therapies for the treatment of angiogenesis associated with tumor growth and wet macular degeneration, systematic investigation of the role of VEGF in the adult retina is critical. Methods and Findings Using immunohistochemistry and Lac-Z reporter mouse lines, we report that VEGF is produced by various cells in the adult mouse retina and that VEGFR2, the primary signaling receptor, is also widely expressed, with strong expression by Müller cells and photoreceptors. Systemic neutralization of VEGF was accomplished in mice by adenoviral expression of sFlt1. After 14 days of VEGF neutralization, there was no effect on the inner and outer retina vasculature, but a significant increase in apoptosis of cells in the inner and outer nuclear layers. By four weeks, the increase in neural cell death was associated with reduced thickness of the inner and outer nuclear layers and a decline in retinal function as measured by electroretinograms. siRNA-based suppression of VEGF expression in a Müller cell line in vitro supports the existence of an autocrine role for VEGF in Müller cell survival. Similarly, the addition of exogenous VEGF to freshly isolated photoreceptor cells and outer-nuclear-layer explants demonstrated VEGF to be highly neuroprotective. Conclusions These results indicate an important role for endogenous VEGF in the maintenance and function of adult retina neuronal cells and indicate that anti-VEGF therapies should be administered with caution.
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            Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease.

            Neonatal chronic lung disease, known as bronchopulmonary dysplasia (BPD), remains a serious complication of prematurity despite advances in the treatment of extremely low birth weight infants. Given the reported protective actions of bone marrow stromal cells (BMSCs; mesenchymal stem cells) in models of lung and cardiovascular injury, we tested their therapeutic potential in a murine model of BPD. Neonatal mice exposed to hyperoxia (75% O(2)) were injected intravenously on Day 4 with either BMSCs or BMSC-conditioned media (CM) and assessed on Day 14 for lung morphometry, vascular changes associated with pulmonary hypertension, and lung cytokine profile. Injection of BMSCs but not pulmonary artery smooth muscle cells (PASMCs) reduced alveolar loss and lung inflammation, and prevented pulmonary hypertension. Although more donor BMSCs engrafted in hyperoxic lungs compared with normoxic controls, the overall low numbers suggest protective mechanisms other than direct tissue repair. Injection of BMSC-CM had a more pronounced effect than BMSCs, preventing both vessel remodeling and alveolar injury. Treated animals had normal alveolar numbers at Day 14 of hyperoxia and a drastically reduced lung neutrophil and macrophage accumulation compared with PASMC-CM-treated controls. Macrophage stimulating factor 1 and osteopontin, both present at high levels in BMSC-CM, may be involved in this immunomodulation. BMSCs act in a paracrine manner via the release of immunomodulatory factors to ameliorate the parenchymal and vascular injury of BPD in vivo. Our study suggests that BMSCs and factor(s) they secrete offer new therapeutic approaches for lung diseases currently lacking effective treatment.
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              The new BPD: an arrest of lung development.

              Alan Jobe (1999)
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                18 November 2016
                2016
                : 11
                : 11
                : e0166886
                Affiliations
                [1 ]Department of Ophthalmology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, United States
                [2 ]Department of Pediatrics, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, United States
                University of Utah (Salt Lake City), UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: AAF KNF.

                • Formal analysis: ML HJC KNF AAF.

                • Funding acquisition: AAF KNF.

                • Investigation: ML HJC RSS.

                • Methodology: HJC JMT KNF ML AAF.

                • Writing – original draft: ML AAF.

                • Writing – review & editing: ML AAF KNF HJC JMT RSS.

                Article
                PONE-D-16-35334
                10.1371/journal.pone.0166886
                5115836
                27861592
                6a50c8ac-e5e7-4290-b451-a4a83606d5f4
                © 2016 Lajko et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 2 September 2016
                : 5 November 2016
                Page count
                Figures: 10, Tables: 1, Pages: 22
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: 5R21HD077336
                Award Recipient :
                Funded by: The Friends of Prentice Grants Initiative of the Northwestern Memorial Foundation
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: CCSG P30 CA060553
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01HL109478
                Award Recipient :
                This work was supported by grants from the National Institutes of Health (5R21HD077336, K.N.F. and A.A.F.; and R01HL109478, K.N.F.) and The Friends of Prentice Grants Initiative of the Northwestern Memorial Foundation (K.N.F.). Histology services were provided by the Northwestern University Research Histology and Phenotyping Laboratory; confocal microscopy was performed at the Northwestern University Center for Advanced Microscopy. Both core facilities are supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Ocular System
                Ocular Anatomy
                Retina
                Medicine and Health Sciences
                Anatomy
                Ocular System
                Ocular Anatomy
                Retina
                Biology and Life Sciences
                Biochemistry
                Glycobiology
                Glycoproteins
                Fibrinogen
                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
                Blood Vessels
                Retinal Vessels
                Medicine and Health Sciences
                Anatomy
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                Blood Vessels
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                Ocular Anatomy
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                Medicine and Health Sciences
                Anatomy
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                Retinal Vessels
                Medicine and Health Sciences
                Ophthalmology
                Retinal Disorders
                Retinal Detachment
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                Physiology
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                Developmental Biology
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                Physical Sciences
                Chemistry
                Chemical Elements
                Oxygen
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                Cell Biology
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                Neurons
                Afferent Neurons
                Retinal Ganglion Cells
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                Neuroscience
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                Neurons
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                Retinal Ganglion Cells
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                Cell Biology
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