NICU, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - Università degli Studi di Milano, Milan, ItalyNICU, Medical and Surgical Feto-Neonatal Department, "A. Meyer" University Children's Hospital, Florence, ItalyDepartment of Biology, Unit of General Physiology, University of Pisa, Pisa, ItalyNeurometabolic Unit, Department of Pediatric Neurosciences, "A. Meyer" University Children's Hospital, Florence, ItalyDepartment of Ophthalmology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
Acta Ophthalmol. 2014 Feb;92(1):2-20. doi: 10.1111/aos.12049. Epub 2013 Apr 26.
Retinopathy of prematurity (ROP) is a disease that can cause blindness in very low birthweight infants. The incidence of ROP is closely correlated with the weight and the gestational age at birth. Despite current therapies, ROP continues to be a highly debilitating disease. Our advancing knowledge of the pathogenesis of ROP has encouraged investigations into new antivasculogenic therapies. The purpose of this article is to review the findings on the pathophysiological mechanisms that contribute to the transition between the first and second phases of ROP and to investigate new potential therapies. Oxygen has been well characterized for the key role that it plays in retinal neoangiogenesis. Low or high levels of pO2 regulate the normal or abnormal production of hypoxia-inducible factor 1 and vascular endothelial growth factors (VEGF), which are the predominant regulators of retinal angiogenesis. Although low oxygen saturation appears to reduce the risk of severe ROP when carefully controlled within the first few weeks of life, the optimal level of saturation still remains uncertain. IGF-1 and Epo are fundamentally required during both phases of ROP, as alterations in their protein levels can modulate disease progression. Therefore, rhIGF-1 and rhEpo were tested for their abilities to prevent the loss of vasculature during the first phase of ROP, whereas anti-VEGF drugs were tested during the second phase. At present, previous hypotheses concerning ROP should be amended with new pathogenetic theories. Studies on the role of genetic components, nitric oxide, adenosine, apelin and β-adrenergic receptor have revealed new possibilities for the treatment of ROP. The genetic hypothesis that single-nucleotide polymorphisms within the β-ARs play an active role in the pathogenesis of ROP suggests the concept of disease prevention using β-blockers. In conclusion, all factors that can mediate the progression from the avascular to the proliferative phase might have significant implications for the further understanding and treatment of ROP.
早产儿视网膜病变（ROP）是一种可导致极低出生体重儿失明的疾病。ROP 的发病率与出生体重和胎龄密切相关。尽管目前已有治疗方法，但 ROP 仍然是一种高度致残的疾病。我们对 ROP 发病机制的认识不断提高，促使人们对新的抗血管生成治疗方法进行了研究。本文旨在回顾导致 ROP 第一和第二阶段转变的病理生理机制的研究结果，并探讨新的潜在治疗方法。
氧在视网膜新生血管形成中起着关键作用，这一点已得到充分证实。低氧或高氧水平调节缺氧诱导因子 1 和血管内皮生长因子（VEGF）的正常或异常产生，VEGF 是视网膜血管生成的主要调节因子。尽管在生命的最初几周内，当氧饱和度得到仔细控制时，低氧饱和度似乎降低了严重 ROP 的风险，但最佳饱和度水平仍不确定。IGF-1 和 Epo 在 ROP 的两个阶段都是基本必需的，因为它们的蛋白水平改变可以调节疾病的进展。因此，rhIGF-1 和 rhEpo 被测试用于在 ROP 的第一阶段预防血管损失，而抗 VEGF 药物则在第二阶段进行了测试。
目前，以前关于 ROP 的假设应该用新的发病理论来修正。有关遗传成分、一氧化氮、腺苷、apelin 和β-肾上腺素能受体作用的研究为 ROP 的治疗提供了新的可能性。β-AR 单核苷酸多态性在 ROP 发病机制中起积极作用的遗传假说表明，使用β-阻滞剂预防疾病的概念。总之，能够介导无血管向增生期进展的所有因素可能对进一步理解和治疗 ROP 具有重要意义。
