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The clinical observation of reduced ROP severity in premature infants after caffeine treatment for apnea suggests that caffeine may protect against ROP. Here, we demonstrate that caffeine did not interfere with normal retinal vascularization development but selectively protected against oxygen\u2010induced retinopathy (OIR) in mice. Moreover, caffeine attenuated not only hypoxia\u2010induced pathologic angiogenesis, but also hyperoxia\u2010induced vaso\u2010obliteration, which suggests a novel protection window by caffeine. At the hyperoxic phase, caffeine reduced oxygen\u2010induced neural apoptosis by adenosine A\n                    <jats:sub>2A<\/jats:sub>\n                    receptor (A\n                    <jats:sub>2A<\/jats:sub>\n                    R)\u2013dependent mechanism, as revealed by combined caffeine and A\n                    <jats:sub>2A<\/jats:sub>\n                    Rknockout treatment. At the hypoxic phase, caffeine reduced microglial activation and enhanced tip cell formation by A\n                    <jats:sub>2A<\/jats:sub>\n                    R\u2010dependent and \u2010independent mechanisms, as combined caffeine and A\n                    <jats:sub>2A<\/jats:sub>\n                    R knockout produced additive and nearly full protection against OIR. Together with clinical use of caffeine in neonates, our demonstration of the selective protection against OIR, effective therapeutic window, adenosine receptor mechanisms, and neuroglial involvement provide the direct evidence of the novel effects of caffeine therapy in the prevention and treatment of ROP.\u2014Zhang, S., Zhou, R., Li, B., Li, H., Wang, Y., Gu, X., Tang, L., Wang, C., Zhong, D., Ge, Y., Huo, Y., Lin, J., Liu, X.\u2010L., Chen, J.\u2010F. Caffeine preferentially protects against oxygen\u2010induced retinopathy.\n                    <jats:italic>FASEB J<\/jats:italic>\n                    . 31, 3334\u20133348 (2017).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201601285r","type":"journal-article","created":{"date-parts":[[2017,4,18]],"date-time":"2017-04-18T20:40:40Z","timestamp":1492548040000},"page":"3334-3348","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Caffeine preferentially protects against oxygen\u2010induced retinopathy"],"prefix":"10.1096","volume":"31","author":[{"given":"Shuya","family":"Zhang","sequence":"first","affiliation":[{"name":"Molecular Neuropharmacology Laboratory School of Optometry and Ophthalmology and Eye Hospital Wenzhou Medical University  Wenzhou 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