Dark-Rearing (DR) precludes the initiating event in OIR and eliminates the pathology seen in the second phase of disease: Rationale for novel non-invasive treatment for ROP

Tailoi Chan-Ling, Nigel L. Barnett, Rita Maccarone, Jan Provis, Mark Koina, Ping Hu, Riccardo Natoli, Silvia Bisti, Robert A. Linsenmeier, Samuel Adamson

Research output: Contribution to journalMeeting AbstractResearchpeer-review

Abstract

Purpose : The initiating event in ROP is delayed retinal vascularization as a consequence of required oxygen supplementation. We hypothesized neonates in high O2 environments should be reared in total darkness, creating a “metabolic sump” via continuous photoreceptor depolarization, eliminating the initiating event in the disease. Methods : 4 groups of SD rats were examined at P14 & P18: 1) Room Air + normal light reared (NLR); 2) Room air + dark rearing (DR). 3) 50/10 OIR + normal light 4) 50/10 OIR + dark rearing. Retinae were examined for vascular density index (VDI), vaso-obliteration & neovascularization, hypoxyprobe-1, astrocyte ensheathment, ultrastructure via TEM and gene expression via qPCR. Electroretinograms (ERG) were recorded at P18 & P25 in OIR, & in long term DR rats (P30/60/90). Retinal O2 profiles were modeled for P14 at 60 & 75% inspired O2 in NLR & DR. Results : Confirming our proof of principle, DR rats had a higher vascular density than NLR rats in room air (VDI=43±1.0 vs.38±1.1 p<0.05 - P7). DR protected vessels from vaso-obliteration (20.6% ± 4.9 v 39.0% ± 4.0 p<0.05). In the hypoxic 2nd phase of OIR, DR reduced pre-retinal neovascularization (4.1% ± 0.9 v 15.8% ± 1.3 p<0.05); tissue hypoxia as evidenced by reduced HP1; protected astrocytes & pericytes from hypoxic damage; and preserved retinal ultrastructure. DR prevented upregulation of HIF1a (65.5% ± 27.2 v -20.4 ± 4.6 p<0.05), VEGF164 (496.6% ± 11.1 v 291.2% ± 60.1 p<0.05) and AP1/Jun (179.8% ± 26.9 v -51.7 ± 16.7, p<0.05) in peripheral retina at P14. DR had no detrimental effects on retinal function as evidenced by ERG at P18 and P25 in OIR, & after long-term DR. O2 profile modeling under DR at 60% inspired O2 at P14 showed that inner retina maintains 'physiological hypoxia' in DR but not in NLR ,whilst 75% O2 overwhelms the protective effect of DR. Conclusions : DR precludes the initiation of ROP by maintaining retinal vascularization during the 1st phase of OIR. As a consequence, when neonates are returned to RA, the retina is protected from hypoxia-induced vaso-proliferation in phase 2 of ROP and it’s associated damaging effects on retinal structure and function. This cost-effective, non-invasive intervention by reducing disease severity can supplement current therapies and, may negate the need for invasive therapies including laser and anti-VEGF. This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
Original languageEnglish
Number of pages3
JournalInvestigative Ophthalmology and Visual Science
Volume57
Issue number12
Publication statusPublished - Sep 2016
Externally publishedYes
EventAnnual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) - Seattle
Duration: 1 May 20165 May 2016

Cite this

Chan-Ling, Tailoi ; Barnett, Nigel L. ; Maccarone, Rita ; Provis, Jan ; Koina, Mark ; Hu, Ping ; Natoli, Riccardo ; Bisti, Silvia ; Linsenmeier, Robert A. ; Adamson, Samuel. / Dark-Rearing (DR) precludes the initiating event in OIR and eliminates the pathology seen in the second phase of disease: Rationale for novel non-invasive treatment for ROP. In: Investigative Ophthalmology and Visual Science. 2016 ; Vol. 57, No. 12.
@article{7c689634beb84074841cd197754f7840,
title = "Dark-Rearing (DR) precludes the initiating event in OIR and eliminates the pathology seen in the second phase of disease: Rationale for novel non-invasive treatment for ROP",
abstract = "Purpose : The initiating event in ROP is delayed retinal vascularization as a consequence of required oxygen supplementation. We hypothesized neonates in high O2 environments should be reared in total darkness, creating a “metabolic sump” via continuous photoreceptor depolarization, eliminating the initiating event in the disease. Methods : 4 groups of SD rats were examined at P14 & P18: 1) Room Air + normal light reared (NLR); 2) Room air + dark rearing (DR). 3) 50/10 OIR + normal light 4) 50/10 OIR + dark rearing. Retinae were examined for vascular density index (VDI), vaso-obliteration & neovascularization, hypoxyprobe-1, astrocyte ensheathment, ultrastructure via TEM and gene expression via qPCR. Electroretinograms (ERG) were recorded at P18 & P25 in OIR, & in long term DR rats (P30/60/90). Retinal O2 profiles were modeled for P14 at 60 & 75{\%} inspired O2 in NLR & DR. Results : Confirming our proof of principle, DR rats had a higher vascular density than NLR rats in room air (VDI=43±1.0 vs.38±1.1 p<0.05 - P7). DR protected vessels from vaso-obliteration (20.6{\%} ± 4.9 v 39.0{\%} ± 4.0 p<0.05). In the hypoxic 2nd phase of OIR, DR reduced pre-retinal neovascularization (4.1{\%} ± 0.9 v 15.8{\%} ± 1.3 p<0.05); tissue hypoxia as evidenced by reduced HP1; protected astrocytes & pericytes from hypoxic damage; and preserved retinal ultrastructure. DR prevented upregulation of HIF1a (65.5{\%} ± 27.2 v -20.4 ± 4.6 p<0.05), VEGF164 (496.6{\%} ± 11.1 v 291.2{\%} ± 60.1 p<0.05) and AP1/Jun (179.8{\%} ± 26.9 v -51.7 ± 16.7, p<0.05) in peripheral retina at P14. DR had no detrimental effects on retinal function as evidenced by ERG at P18 and P25 in OIR, & after long-term DR. O2 profile modeling under DR at 60{\%} inspired O2 at P14 showed that inner retina maintains 'physiological hypoxia' in DR but not in NLR ,whilst 75{\%} O2 overwhelms the protective effect of DR. Conclusions : DR precludes the initiation of ROP by maintaining retinal vascularization during the 1st phase of OIR. As a consequence, when neonates are returned to RA, the retina is protected from hypoxia-induced vaso-proliferation in phase 2 of ROP and it’s associated damaging effects on retinal structure and function. This cost-effective, non-invasive intervention by reducing disease severity can supplement current therapies and, may negate the need for invasive therapies including laser and anti-VEGF. This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.",
author = "Tailoi Chan-Ling and Barnett, {Nigel L.} and Rita Maccarone and Jan Provis and Mark Koina and Ping Hu and Riccardo Natoli and Silvia Bisti and Linsenmeier, {Robert A.} and Samuel Adamson",
year = "2016",
month = "9",
language = "English",
volume = "57",
journal = "Investigative Ophthalmology",
issn = "0146-0404",
publisher = "ASSOC RESEARCH VISION OPHTHALMOLOGY INC",
number = "12",

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Dark-Rearing (DR) precludes the initiating event in OIR and eliminates the pathology seen in the second phase of disease: Rationale for novel non-invasive treatment for ROP. / Chan-Ling, Tailoi; Barnett, Nigel L.; Maccarone, Rita; Provis, Jan; Koina, Mark; Hu, Ping; Natoli, Riccardo; Bisti, Silvia; Linsenmeier, Robert A.; Adamson, Samuel.

In: Investigative Ophthalmology and Visual Science, Vol. 57, No. 12, 09.2016.

Research output: Contribution to journalMeeting AbstractResearchpeer-review

TY - JOUR

T1 - Dark-Rearing (DR) precludes the initiating event in OIR and eliminates the pathology seen in the second phase of disease: Rationale for novel non-invasive treatment for ROP

AU - Chan-Ling, Tailoi

AU - Barnett, Nigel L.

AU - Maccarone, Rita

AU - Provis, Jan

AU - Koina, Mark

AU - Hu, Ping

AU - Natoli, Riccardo

AU - Bisti, Silvia

AU - Linsenmeier, Robert A.

AU - Adamson, Samuel

PY - 2016/9

Y1 - 2016/9

N2 - Purpose : The initiating event in ROP is delayed retinal vascularization as a consequence of required oxygen supplementation. We hypothesized neonates in high O2 environments should be reared in total darkness, creating a “metabolic sump” via continuous photoreceptor depolarization, eliminating the initiating event in the disease. Methods : 4 groups of SD rats were examined at P14 & P18: 1) Room Air + normal light reared (NLR); 2) Room air + dark rearing (DR). 3) 50/10 OIR + normal light 4) 50/10 OIR + dark rearing. Retinae were examined for vascular density index (VDI), vaso-obliteration & neovascularization, hypoxyprobe-1, astrocyte ensheathment, ultrastructure via TEM and gene expression via qPCR. Electroretinograms (ERG) were recorded at P18 & P25 in OIR, & in long term DR rats (P30/60/90). Retinal O2 profiles were modeled for P14 at 60 & 75% inspired O2 in NLR & DR. Results : Confirming our proof of principle, DR rats had a higher vascular density than NLR rats in room air (VDI=43±1.0 vs.38±1.1 p<0.05 - P7). DR protected vessels from vaso-obliteration (20.6% ± 4.9 v 39.0% ± 4.0 p<0.05). In the hypoxic 2nd phase of OIR, DR reduced pre-retinal neovascularization (4.1% ± 0.9 v 15.8% ± 1.3 p<0.05); tissue hypoxia as evidenced by reduced HP1; protected astrocytes & pericytes from hypoxic damage; and preserved retinal ultrastructure. DR prevented upregulation of HIF1a (65.5% ± 27.2 v -20.4 ± 4.6 p<0.05), VEGF164 (496.6% ± 11.1 v 291.2% ± 60.1 p<0.05) and AP1/Jun (179.8% ± 26.9 v -51.7 ± 16.7, p<0.05) in peripheral retina at P14. DR had no detrimental effects on retinal function as evidenced by ERG at P18 and P25 in OIR, & after long-term DR. O2 profile modeling under DR at 60% inspired O2 at P14 showed that inner retina maintains 'physiological hypoxia' in DR but not in NLR ,whilst 75% O2 overwhelms the protective effect of DR. Conclusions : DR precludes the initiation of ROP by maintaining retinal vascularization during the 1st phase of OIR. As a consequence, when neonates are returned to RA, the retina is protected from hypoxia-induced vaso-proliferation in phase 2 of ROP and it’s associated damaging effects on retinal structure and function. This cost-effective, non-invasive intervention by reducing disease severity can supplement current therapies and, may negate the need for invasive therapies including laser and anti-VEGF. This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

AB - Purpose : The initiating event in ROP is delayed retinal vascularization as a consequence of required oxygen supplementation. We hypothesized neonates in high O2 environments should be reared in total darkness, creating a “metabolic sump” via continuous photoreceptor depolarization, eliminating the initiating event in the disease. Methods : 4 groups of SD rats were examined at P14 & P18: 1) Room Air + normal light reared (NLR); 2) Room air + dark rearing (DR). 3) 50/10 OIR + normal light 4) 50/10 OIR + dark rearing. Retinae were examined for vascular density index (VDI), vaso-obliteration & neovascularization, hypoxyprobe-1, astrocyte ensheathment, ultrastructure via TEM and gene expression via qPCR. Electroretinograms (ERG) were recorded at P18 & P25 in OIR, & in long term DR rats (P30/60/90). Retinal O2 profiles were modeled for P14 at 60 & 75% inspired O2 in NLR & DR. Results : Confirming our proof of principle, DR rats had a higher vascular density than NLR rats in room air (VDI=43±1.0 vs.38±1.1 p<0.05 - P7). DR protected vessels from vaso-obliteration (20.6% ± 4.9 v 39.0% ± 4.0 p<0.05). In the hypoxic 2nd phase of OIR, DR reduced pre-retinal neovascularization (4.1% ± 0.9 v 15.8% ± 1.3 p<0.05); tissue hypoxia as evidenced by reduced HP1; protected astrocytes & pericytes from hypoxic damage; and preserved retinal ultrastructure. DR prevented upregulation of HIF1a (65.5% ± 27.2 v -20.4 ± 4.6 p<0.05), VEGF164 (496.6% ± 11.1 v 291.2% ± 60.1 p<0.05) and AP1/Jun (179.8% ± 26.9 v -51.7 ± 16.7, p<0.05) in peripheral retina at P14. DR had no detrimental effects on retinal function as evidenced by ERG at P18 and P25 in OIR, & after long-term DR. O2 profile modeling under DR at 60% inspired O2 at P14 showed that inner retina maintains 'physiological hypoxia' in DR but not in NLR ,whilst 75% O2 overwhelms the protective effect of DR. Conclusions : DR precludes the initiation of ROP by maintaining retinal vascularization during the 1st phase of OIR. As a consequence, when neonates are returned to RA, the retina is protected from hypoxia-induced vaso-proliferation in phase 2 of ROP and it’s associated damaging effects on retinal structure and function. This cost-effective, non-invasive intervention by reducing disease severity can supplement current therapies and, may negate the need for invasive therapies including laser and anti-VEGF. This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

M3 - Meeting Abstract

VL - 57

JO - Investigative Ophthalmology

JF - Investigative Ophthalmology

SN - 0146-0404

IS - 12

ER -