title: The pathophysiology of retinopathy of prematurity: an update of previous and recent knowledge.
abstract: 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.
authors.affiliation: 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.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Cavallaro
authors.forename: Luca
authors.initials: L
authors.lastname: Filippi
authors.forename: Paola
authors.initials: P
authors.lastname: Bagnoli
authors.forename: Giancarlo
authors.initials: G
authors.lastname: La Marca
authors.forename: Gloria
authors.initials: G
authors.lastname: Cristofori
authors.forename: Genny
authors.initials: G
authors.lastname: Raffaeli
authors.forename: Letizia
authors.initials: L
authors.lastname: Padrini
authors.forename: Gabriella
authors.initials: G
authors.lastname: Araimo
authors.forename: Monica
authors.initials: M
authors.lastname: Fumagalli
authors.forename: Michela
authors.initials: M
authors.lastname: Groppo
authors.forename: Massimo
authors.initials: M
authors.lastname: Dal Monte
authors.forename: Silvia
authors.initials: S
authors.lastname: Osnaghi
authors.forename: Patrizio
authors.initials: P
authors.lastname: Fiorini
authors.forename: Fabio
authors.initials: F
authors.lastname: Mosca
mesh_terms: D005865:Gestational Age; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D007223:Infant; D007231:Infant, Newborn; D019102:Infant, Very Low Birth Weight; D010100:Oxygen / Q000502:physiology; D012178:Retinopathy of Prematurity / Q000378:metabolism / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D051793:Hypoxia-Inducible Factor 1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D010100:Oxygen
keywords: erythropoietin; hypoxia-inducible factor 1; insulin-like growth factor-1; neovascularization; pathophysiology; placental growth factor; retinopathy of prematurity; vascular endothelial growth factor; β-adrenergic receptors