Retinopathy of prematurity: contribution of inflammatory and genetic factors

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.

GSDMD deficiency ameliorates hyperoxia-induced BPD and ROP in neonatal mice

“…Microglial cells play active roles in maintaining the normal structure and functioning of the retina. In a chronic pre-inflammatory environment, microglia become pathologically activated and release excessive inflammatory mediators that promote retina damage and disease progression [43][44][45][46] . Preventing chronic microglial activation by GSDMD-KO would certainly reduce retina injury and progression of ROP caused by chronic hyperoxia exposure.…”

Potential biomarkers for retinopathy of prematurity identified by circular RNA profiling in peripheral blood mononuclear cells

“…Using GO analysis, we found that the host genes of the down-regulated circRNAs were enriched in oxygen transport and binding. ROP is induced by hypoxia leading to pathological neovascularization, and oxygen plays an important role in the pathogenesis of ROP ( 36 ). An in vivo study indicated that hyperoxia treatment is a useful therapeutic strategy in targeting pathological neovascularization in ischemic retinopathy, and does not have the inflammatory effect related to anti-VEGF therapies ( 37 ).…”

“…The ceRNA regulatory network constructed in the current study identified numerous miRNAs and target genes, and GO and KEGG analyses identified key biological processes such as “regulation of cytokine secretion”. Many cytokines, such as IL-12, IL-17 and IL-23 have been found to have fundamental roles in ocular angiogenesis and ROP pathogenesis ( 36 , 41 – 43 ). Therefore, the present results of bioinformatics analysis are consistent with previous findings, and indicate that circRNAs may play a regulatory role in the effect of cytokines on angiogenesis.…”

Systemic Cytokines in Retinopathy of Prematurity

“…Estimated heritability for susceptibility to ROP has been reported to be approximately 70–73% [ 410 , 411 ]. Several candidate genes modulating downstream inflammatory and angiogenic pathways leading to ROP have been identified [ 413 ] and may potentially become targets of novel therapeutics.…”