Research progress on oxidative stress in the pathogenesis and treatment of retinopathy of prematurity_Chinese Journal of Ocular Fundus Diseases

Authors：

Xixiang Wei ,  Hui Yang , Xue Yin , Zheng Fu , Weiwei Xiong

Department of Ophthalmology, Xiamen Children's Hospital (Children's Hospital of Fudan University at Xiamen), Xiamen 361000, China;

Corresponding author：

Hui Yang, Email: 805992715@qq.com

Keywords：

Retinopathy of Prematurity; Oxidative Stress; Pathogenesis; Therapeutic Targets; Review

DOI：

10.3760/cma.j.cn511434-20250402-00147

Video：

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Abstract Full text Figures/Tables Video References Cited by

Retinopathy of Prematurity (ROP) is a blinding eye disease characterized by abnormal retinal vascular proliferation and is a major cause of visual impairment in children. Its pathogenesis is complex, involving multiple factors such as hyperoxia exposure, hypoxic compensation, oxidative stress, inflammatory responses, and abnormal angiogenesis, with oxidative stress playing a central role. It is characterized by excessive production of reactive oxygen species and impaired antioxidant function, leading to retinal vascular endothelial cell damage, formation of avascular areas, and abnormal vascular proliferation. Studies have shown that oxidative stress can promote the development and progression of ROP through vascular damage, nitrooxidative stress synergy, and interference with cellular metabolism. Current treatment strategies mainly include antioxidant agents (such as vitamin C, vitamin E, and lutein), signal pathway regulatory agents (such as nuclear factor erythroid 2-related factor 2 activators, signal transducer and activator of transcription 3 inhibitors), corticosteroids (such as Triamcinolone and Dexamethasone), and adrenergic receptor antagonists (such as Propranolol), but their efficacy and safety still require further validation. In the future, multidisciplinary collaboration should be strengthened to further explore the interactions between oxidative stress and other pathological mechanisms, and long-term follow-up studies should be conducted to develop safer and more effective strategies for the prevention and treatment of ROP, thereby improving the visual outcomes of preterm infants.

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1. Dammann O, Hartnett ME, Stahl A. Retinopathy of prematurity[J]. Dev Med Child Neurol, 2023, 65(5): 625-631. DOI: 10.1111/dmcn.15468.
2. Fevereiro-Martins M, Marques-Neves C, Guimarães H, et al. Retinopathy of prematurity: a review of pathophysiology and signaling pathways[J]. Surv Ophthalmol, 2023, 68(2): 175-210. DOI: 10.1016/j.survophthal.2022.11.007.
3. Sabri K, Ells AL, Lee EY, et al. Retinopathy of prematurity: a global perspective and recent developments[J/OL]. Pediatrics, 2022, 150(3): e2021053924[2022-09-01]. https://pubmed.ncbi.nlm.nih.gov/35948728/. DOI: 10.1542/peds.2021-053924.
4. Nebbioso M, Franzone F, Lambiase A, et al. Oxidative stress implication in retinal diseases-a review[J/OL]. Antioxidants (Basel), 2022, 11(9): 1790[2022-09-10]. https://pubmed.ncbi.nlm.nih.gov/36139862/. DOI: 10.3390/antiox11091790.
5. Li C, Miao X, Li F, et al. Oxidative stress-related mechanisms and antioxidant therapy in diabetic retinopathy[J/OL]. Oxid Med Cell Longev, 2017, 2017: 9702820[2017-02-06]. https://pubmed.ncbi.nlm.nih.gov/28265339/. DOI: 10.1155/2017/9702820.
6. Wang X, Wang T, Lam E, et al. Ocular vascular diseases: from retinal immune privilege to inflammation[J/OL]. Int J Mol Sci, 2023, 24(15): 12090[2023-07-28]. https://pubmed.ncbi.nlm.nih.gov/37569464/. DOI: 10.3390/ijms241512090.
7. Nishinaka A, Inoue Y, Fuma S, et al. Pathophysiological role of VEGF on retinal edema and nonperfused areas in mouse eyes with retinal vein occlusion[J]. Invest Ophthalmol Vis Sci, 2018, 59(11): 4701-4713. DOI: 10.1167/iovs.18-23994.
8. Sharma S, Saxena S, Srivastav K, et al. Nitric oxide and oxidative stress is associated with severity of diabetic retinopathy and retinal structural alterations[J]. Clin Exp Ophthalmol, 2015, 43(5): 429-436. DOI: 10.1111/ceo.12506.
9. Ruan Y, Jiang S, Musayeva A, et al. Oxidative stress and vascular dysfunction in the retina: therapeutic strategies[J/OL]. Antioxidants (Basel), 2020, 9(8): 761[2020-08-17]. https://pubmed.ncbi.nlm.nih.gov/32824523/. DOI: 10.3390/antiox9080761.
10. Gericke A, Buonfiglio F. Physiological and pathophysiological relevance of nitric oxide synthases (NOS) in retinal blood vessels[J/OL]. Front Biosci (Landmark Ed), 2024, 29(5): 190[2024-05-16]. https://pubmed.ncbi.nlm.nih.gov/38812321/. DOI: 10.31083/j.fbl2905190.
11. Penn JS, Madan A, Caldwell RB, et al. Vascular endothelial growth factor in eye disease[J]. Prog Retin Eye Res, 2008, 27(4): 331-371. DOI: 10.1016/j.preteyeres.2008.05.001.
12. Cung T, Wang H, Hartnett ME. The effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and erythropoietin, and their interactions in angiogenesis: implications in retinopathy of prematurity[J/OL]. Cells, 2022, 11(12): 1951[2022-06-17]. https://pubmed.ncbi.nlm.nih.gov/35741081/. DOI: 10.3390/cells11121951.
13. Wang H, Zhang SX, Hartnett ME. Signaling pathways triggered by oxidative stress that mediate features of severe retinopathy of prematurity[J]. JAMA Ophthalmol, 2013, 131(1): 80-85. DOI: 10.1001/jamaophthalmol.2013.986.
14. Kermorvant-Duchemin E, Sennlaub F, Sirinyan M, et al. Trans-arachidonic acids generated during nitrative stress induce a thrombospondin-1-dependent microvascular degeneration[J]. Nat Med, 2005, 11(12): 1339-1345. DOI: 10.1038/nm1336.
15. Gu X, El-Remessy AB, Brooks SE, et al. Hyperoxia induces retinal vascular endothelial cell apoptosis through formation of peroxynitrite[J]. Am J Physiol Cell Physiol, 2003, 285(3): 546-554. DOI: 10.1152/ajpcell.00424.2002.
16. Wilkinson-Berka JL, Deliyanti D, Rana I, et al. NADPH oxidase, NOX1, mediates vascular injury in ischemic retinopathy[J]. Antioxid Redox Signal, 2014, 20(17): 2726-2740. DOI: 10.1089/ars.2013.5357.
17. Edgar KS, Matesanz N, Gardiner TA, et al. Hyperoxia depletes (6R)-5, 6, 7, 8-tetrahydrobiopterin levels in the neonatal retina: implications for nitric oxide synthase function in retinopathy[J]. Am J Pathol, 2015, 185(6): 1769-1782. DOI: 10.1016/j.ajpath.2015.02.021.
18. Wang J, Li M, Geng Z, et al. Role of oxidative stress in retinal disease and the early intervention strategies: a review[J/OL]. Oxid Med Cell Longev, 2022, 2022: 7836828[2022-10-14]. https://pubmed.ncbi.nlm.nih.gov/36275903/. DOI: 10.1155/2022/7836828.
19. Barnett JM, McCollum GW, Penn JS. Role of cytosolic phospholipase A(2) in retinal neovascularization[J]. Invest Ophthalmol Vis Sci, 2010, 51(2): 1136-1142. DOI: 10.1167/iovs.09-3691.
20. Joyal JS, Sun Y, Gantner ML, et al. Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1[J]. Nat Med, 2016, 22(4): 439-445. DOI: 10.1038/nm.4059.
21. Su S, Zou P, Yang G, et al. Propranolol ameliorates retinopathy of prematurity in mice by downregulating HIF-1alpha via the PI3K/Akt/ERK pathway[J]. Pediatr Res, 2023, 93(5): 1250-1257. DOI: 10.1038/s41390-022-02211-8.
22. Wang Q, Zhu M, Li W, et al. CBX7 promotes choroidal neovascularization by activating the HIF-1alpha/VEGF pathway in choroidal vascular endothelial cells[J/OL]. Exp Eye Res, 2024, 247: 110057[2024-08-22]. https://pubmed.ncbi.nlm.nih.gov/39179168/. DOI: 10.1016/j.exer.2024.110057.
23. Tsai AS, Chou HD, Ling XC, et al. Assessment and management of retinopathy of prematurity in the era of anti-vascular endothelial growth factor (VEGF)[J/OL]. Prog Retin Eye Res, 2022, 88: 101018[2021-11-09]. https://pubmed.ncbi.nlm.nih.gov/34763060/. DOI: 10.1016/j.preteyeres.2021.101018.
24. McPherson C. Eyesight to the blind-pharmacotherapy for retinopathy of prematurity[J]. Neonatal Netw, 2023, 42(2): 88-95. DOI: 10.1891/nn.2022-0054.
25. Sauer L, Chandler M, Hartnett ME. Extending peripheral retinal vascularization in retinopathy of prematurity through regulation of VEGF signaling[J]. Am J Ophthalmol, 2024, 260: 190-199. DOI: 10.1016/j.ajo.2023.12.008.
26. Ling XC, Kang EY, Chen KJ, et al. Associations of VEGF polymorphisms with retinopathy of prematurity[J]. Invest Ophthalmol Vis Sci, 2023, 64(7): 11. DOI: 10.1167/iovs.64.7.11.
27. Graziosi A, Perrotta M, Russo D, et al. Oxidative stress markers and the retinopathy of prematurity[J/OL]. J Clin Med, 2020, 9(9): 2711[2020-08-21]. https://pubmed.ncbi.nlm.nih.gov/32825796/. DOI: 10.3390/jcm9092711.
28. Tsang JKW, Liu J, Lo ACY. Vascular and neuronal protection in the developing retina: potential therapeutic targets for retinopathy of prematurity[J/OL]. Int J Mol Sci, 2019, 20(17): 4321[2019-09-03]. https://pubmed.ncbi.nlm.nih.gov/31484463/. DOI: 10.3390/ijms20174321.
29. Romero-Maldonado S, Montoya-Estrada A, Reyes-Muñoz E, et al. Efficacy of water-based vitamin E solution versus placebo in the prevention of retinopathy of prematurity in very low birth weight infants: a randomized clinical trial[J/OL]. Medicine (Baltimore), 2021, 100(31): e26765[2021-08-06]. https://pubmed.ncbi.nlm.nih.gov/34397821/. DOI: 10.1097/md.0000000000026765.
30. Hellström A, Nilsson AK, Wackernagel D, et al. Effect of enteral lipid supplement on severe retinopathy of prematurity: a randomized clinical trial[J]. JAMA Pediatr, 2021, 175(4): 359-367. DOI: 10.1001/jamapediatrics.2020.5653.
31. Uno K, Prow TW, Bhutto IA, et al. Role of Nrf2 in retinal vascular development and the vaso-obliterative phase of oxygen-induced retinopathy[J]. Exp Eye Res, 2010, 90(4): 493-500. DOI: 10.1016/j.exer.2009.12.012.
32. Deliyanti D, Lee JY, Petratos S, et al. A potent Nrf2 activator, dh404, bolsters antioxidant capacity in glial cells and attenuates ischaemic retinopathy[J]. Clin Sci (Lond), 2016, 130(15): 1375-1387. DOI: 10.1042/cs20160068.
33. Bartoli M, Al-Shabrawey M, Labazi M, et al. HMG-CoA reductase inhibitors (statin) prevents retinal neovascularization in a model of oxygen-induced retinopathy[J]. Invest Ophthalmol Vis Sci, 2009, 50(10): 4934-4940. DOI: 10.1167/iovs.08-2158.
34. Chen S, Sun Q, Sun D, et al. C-CBL is required for inhibition of angiogenesis through modulating JAK2/STAT3 activity in ROP development[J/OL]. Biomed Pharmacother, 2020, 132: 110856[2020-10-28]. https://pubmed.ncbi.nlm.nih.gov/33125970/. DOI: 10.1016/j.biopha.2020.110856.
35. Ren J, Jiang J, Ou W, et al. The effect of STAT3 signal pathway activation on retinopathy of prematurity[J/OL]. Front Pediatr, 2021, 9: 638432[2021-11-10]. https://pubmed.ncbi.nlm.nih.gov/34858895/. DOI: 10.3389/fped.2021.638432.
36. Chen S, Zhang J, Sun D, et al. SYVN1 promotes STAT3 protein ubiquitination and exerts antiangiogenesis effects in retinopathy of prematurity development[J/OL]. Invest Ophthalmol Vis Sci, 2023, 64(11): 8[2023-08-01]. https://pubmed.ncbi.nlm.nih.gov/37540175/. DOI: 10.1167/iovs.64.11.8.
37. Jiang J, Xia XB, Xu HZ, et al. Inhibition of retinal neovascularization by gene transfer of small interfering RNA targeting HIF-1alpha and VEGF[J]. J Cell Physiol, 2009, 218(1): 66-74. DOI: 10.1002/jcp.21566.
38. Usui-Ouchi A, Aguilar E, Murinello S, et al. An allosteric peptide inhibitor of HIF-1alpha regulates hypoxia-induced retinal neovascularization[J]. Proc Natl Acad Sci USA, 2020, 117(45): 28297-28306. DOI: 10.1073/pnas.2017234117.
39. Huang YH, Kuo CH, Peng IC, et al. Recombinant thrombomodulin domain 1 rescues pathological angiogenesis by inhibition of HIF-1alpha-VEGF pathway[J]. Cell Mol Life Sci, 78(23): 7681-7692. DOI: 10.1007/s00018-021-03950-3.
40. Zhang L, Buonfiglio F, Fieß A, et al. Retinopathy of prematurity-targeting hypoxic and redox signaling pathways[J/OL]. Antioxidants (Basel), 2024, 13(2): 148[2024-01-25]. https://pubmed.ncbi.nlm.nih.gov/38397746/. DOI: 10.3390/antiox13020148.
41. May CA. The influence of triamcinolone on endostatin-like proteins in oxygen-induced retinopathy of prematurity[J]. Exp Eye Res, 2012, 100: 86-87. DOI: 10.1016/j.exer.2012.04.017.
42. Öhnell HM, Andreasson S, Gränse L. Dexamethasone eye drops for the treatment of retinopathy of prematurity[J]. Ophthalmol Retina, 2022, 6(2): 181-182. DOI: 10.1016/j.oret.2021.09.002.
43. Shekhawat PS, Ali MAM, Kannekanti N, et al. Impact of postnatal steroids on peripheral avascular retina and severity of retinopathy of prematurity[J]. Pediatr Res, 2023, 94(6): 1966-1972. DOI: 10.1038/s41390-023-02673-4.
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