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Retinopathy of prematurity: contribution of inflammatory and genetic factors

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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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Abbreviations

AA:

Arachidonic acid

ADAM:

“A” disintegrin and metalloproteinase

ANGs:

Angiopoietins

BDNF:

Brain-derived neurotrophic factor

bFGF:

Basic fibroblast growth factor

BH4:

Tetrahydrobiopterin

BV:

Blood vessels

BW:

Birth weight

EC:

Endothelial cells

eNOS:

Endothelial nitric oxide synthase

ECM:

Extracellular matrix

EPAS1:

Endothelial PAS Domain Protein 1

EPO:

Erythropoietin

FEVR:

Familial exudative vitreoretinopathy

GA:

Gestational age

HIF:

Hypoxia-inducible factor

HMOX-1:

Heme oxygenase 1

ICAM-1:

Intercellular adhesion molecule-1

IFN-γ:

Interferon gamma

IGF-1:

Insulin-like growth factor 1

IL:

Interleukin

IL-1Ra:

Interleukin 1 receptor antagonist

iNOS:

Inducible nitric oxide synthase

I-TAC:

Interferon-inducible T-cell alpha chemoattractant

LPS:

Lipopolysaccharide

MCP-1:

Monocyte chemotactic protein 1

MMPs:

Matrix metalloproteinases

NGF:

Nerve growth factor

NTs:

Neurotrophins

OIR:

Oxygen-induced retinopathy

OS:

Oxidative stress

PC:

Prostacyclin

PDGF:

Platelet-derived growth factor

PGs:

Prostaglandins

PLA2:

Phospholipase A2

PLGF:

Placental growth factor

PPARγ:

Proliferator-activated receptor gamma

PTI:

Preterm infants

RANTES:

Regulated on activation, normal T cell expressed and secreted

ROP:

Retinopathy of prematurity

ROS:

Reactive oxygen species

Sema3A:

Semaphoring 3A

SNPs:

Single-nucleotide polymorphisms

TA:

Thromboxane

TGF-β:

Transforming growth factor beta

TNF-α:

Tumor necrosis factor alpha

Trk:

Tropomyosin kinase

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

Wk:

Weeks

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Acknowledgments

Special thanks to Ana Carolina Santos for her support in this work.

Funding

This work was supported by the Laboratório de Genética and the Instituto de Saúde Ambiental (ISAMB) of the Faculdade de Medicina of Universidade de Lisboa and the Instituto de Investigação Científica Bento da Rocha Cabral. The writing of the manuscript was also supported by funds from Fundação para a Ciência e a Tecnologia to ISAMB (ref. UIDB/04295/2020 and UIDP/04295/2020).

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Authors and Affiliations

  1. Laboratório de Genética and Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, Av. Professor Egas Moniz, Piso 1C, 1649-028, Lisboa, Portugal

    Mariza Fevereiro-Martins, Carlos Marques-Neves & Manuel Bicho

  2. Instituto de Investigação Científica Bento da Rocha Cabral, Calçada Bento da Rocha Cabral 14, 1250-012, Lisboa, Portugal

    Mariza Fevereiro-Martins & Manuel Bicho

  3. Departamento de Oftalmologia, Hospital Cuf Descobertas, Rua Mário Botas, 1998-018, Lisboa, Portugal

    Mariza Fevereiro-Martins

  4. Centro de Estudos das Ciências da Visão, Faculdade de Medicina, Universidade de Lisboa, Av. Professor Egas Moniz, Piso 1C, 1649-028, Lisboa, Portugal

    Carlos Marques-Neves

  5. Departamento de Ginecologia- Obstetrícia e Pediatria, Faculdade de Medicina, Universidade do Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal

    Hercília Guimarães

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  1. Mariza Fevereiro-Martins
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The first draft of the manuscript was written by Mariza Fevereiro-Martins. Mariza Fevereiro-Martins and Manuel Bicho had the idea for the article. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Mariza Fevereiro-Martins.

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Fevereiro-Martins, M., Guimarães, H., Marques-Neves, C. et al. Retinopathy of prematurity: contribution of inflammatory and genetic factors. Mol Cell Biochem 477, 1739–1763 (2022). https://doi.org/10.1007/s11010-022-04394-4

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