TY - JOUR
T1 - Caffeine preferentially protects against oxygen-induced retinopathy
AU - Zhang, Shuya
AU - Zhou, Rong
AU - Li, Bo
AU - Li, Haiyan
AU - Wang, Yanyan
AU - Gu, Xuejiao
AU - Tang, Lingyun
AU - Wang, Cun
AU - Zhong, Dingjuan
AU - Ge, Yuanyuan
AU - Huo, Yuqing
AU - Lin, Jing
AU - Liu, Xiao Ling
AU - Chen, Jiang Fan
N1 - Funding Information:
This study was sponsored by the Start-up Fund from Wenzhou Medical University (Grants 89211010 and 89212012 to J.-F.C.), the National Natural Science Foundation of China (Grants 81630040 to J.-F.C., 81600753 to S.Z., and 81100672 to R.Z.), the Zhejiang Provincial Special Funds (Grant 604161241 to J.-F.C.), Key Laboratory of Vision Science, Ministry of Health, China (Grant 601041241 to J.-F.C.), the National Key Basic Research Program of China (Grant 2012CB910402 to J.-F.C.), the Central Government Special Fund for Local Universities’ Development (Grant 474091314 to J.-F.C.), and Zhejiang Provincial Natural Science Foundation (Grant LY12H12007 to X.-L.L.). This study was also funded by U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (Grant DK095862 to Y.H.), NIH National Heart, Lung, and Blood Institute (Grants HL095556 and HL108922 to Y.H.), and Boston University School of Medicine Special Research Fund DTD 4-30-14 (to J.-F.C.). The authors thank Dr. Zailong Chi (Wenzhou Medical University) for critical reading of the manuscript, and Drs. Zhe Wang and Congcong Wen (both from Wenzhou Medical University) for assistance in ultra-high-performance liquid chromatography–mass spectrometry analysis.
Publisher Copyright:
© FASEB.
PY - 2017/8
Y1 - 2017/8
N2 - Retinopathy of prematurity (ROP) is the leading cause of childhood blindness, but current anti-VEGF therapy is concerned with delayed retinal vasculature, eye, and brain development of preterm infants. 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-induced retinopathy (OIR) in mice. Moreover, caffeine attenuated not only hypoxia-induced pathologic angiogenesis, but also hyperoxia-induced vaso-obliteration, which suggests a novel protection window by caffeine. At the hyperoxic phase, caffeine reduced oxygen-induced neural apoptosis by adenosine A2A receptor (A2AR)–dependent mechanism, as revealed by combined caffeine and A2AR-knockout treatment. At the hypoxic phase, caffeine reduced microglial activation and enhanced tip cell formation by A2AR-dependent and -independent mechanisms, as combined caffeine and A2AR 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.—Zhang, 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.-L., Chen, J.-F. Caffeine preferentially protects against oxygen-induced retinopathy.
AB - Retinopathy of prematurity (ROP) is the leading cause of childhood blindness, but current anti-VEGF therapy is concerned with delayed retinal vasculature, eye, and brain development of preterm infants. 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-induced retinopathy (OIR) in mice. Moreover, caffeine attenuated not only hypoxia-induced pathologic angiogenesis, but also hyperoxia-induced vaso-obliteration, which suggests a novel protection window by caffeine. At the hyperoxic phase, caffeine reduced oxygen-induced neural apoptosis by adenosine A2A receptor (A2AR)–dependent mechanism, as revealed by combined caffeine and A2AR-knockout treatment. At the hypoxic phase, caffeine reduced microglial activation and enhanced tip cell formation by A2AR-dependent and -independent mechanisms, as combined caffeine and A2AR 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.—Zhang, 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.-L., Chen, J.-F. Caffeine preferentially protects against oxygen-induced retinopathy.
KW - Adenosine A2A receptor
KW - Neovascularization
KW - Retinopathy of prematurity
KW - Vaso-obliteration
UR - http://www.scopus.com/inward/record.url?scp=85026817266&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85026817266&partnerID=8YFLogxK
U2 - 10.1096/fj.201601285R
DO - 10.1096/fj.201601285R
M3 - Article
C2 - 28420694
AN - SCOPUS:85026817266
SN - 0892-6638
VL - 31
SP - 3334
EP - 3348
JO - FASEB Journal
JF - FASEB Journal
IS - 8
ER -