Proliferative Retinopathy Is Associated with Impaired Increase in BDNF and RANTES Expression Levels after Preterm Birth

Abstract

Background: Extremely preterm delivery is, amongst other complications, associated with retinopathy of prematurity (ROP). Untreated, ROP can progress to visual impairment and blindness due to an overgrowth of new vessels in the retina and vitreous cavity. Objective: The aim of this study was to identify cytokine markers within the first weeks of life that could be used to predict the risk for development of ROP later in life. Methods: Serum levels of 27 different cytokines in infants born at gestational weeks 23–30 were analyzed using a multiplex immunoassay method and compared between infants who did not develop ROP and infants who later developed proliferative ROP. In addition, mRNA levels of brain-derived neurotrophic factor (BDNF) in retinas from mice exposed to hyperoxia were analyzed using quantitative real-time PCR. Results: At birth, serum levels of IL-5 were higher in infants with no ROP compared to infants with proliferative ROP. 10–14 days after birth, serum levels of BDNF and RANTES were lower in infants who later developed proliferative ROP compared to infants who did not develop ROP. Furthermore, mRNA expression levels of BDNF in retinas from mice exposed to hyperoxia were significantly lower at postnatal day 15 compared to retinas from mice in room air. Conclusions: These results indicate that BDNF and RANTES may be important factors in the selective vulnerability of ROP development in preterm infants.

Systemic inflammation associated with severe intestinal injury in extremely low gestational age newborns

“…46 Others have found that low CCL5 concentrations in the blood are associated with increased risk of proliferative retinopathy of prematurity. 47 Thus, our finding that infants who developed NEC tended to have low CCL5 concentrations in the blood is in keeping with the view that high concentrations of CCL5 reduce the risk of inflammation-related disorders in the very preterm newborn.…”

Genetic Variants Associated With Severe Retinopathy of Prematurity in Extremely Low Birth Weight Infants

“…There is strong clinical evidence of reduced circulating BDNF levels in severe ROP. 34,43,44 Blood spot samples of infants from the same population as the discovery cohort in this report were analyzed for cytokines, 34 and reduced serum protein BDNF was found associated with severe ROP. 34 Although low serum BDNF in the cytokine analysis cannot be causally related to the intronic BDNF SNP variants reported here, the finding of reduced BDNF protein in the same cohort as the discovery cohort supports the thinking that variants in BDNF may be important in the pathophysiology of severe ROP.…”

“…In a separate study from Sweden, serum BDNF and RANTES levels measured within 14 days of birth were lower in preterm infants who developed severe ROP than in those who did not. 44 However, to determine if the intronic variants we report in BDNF affect protein function and biologic outcomes, deep sequencing of the gene in future nonbiased human studies and studies in cultured cells and/or animal models must be performed.…”

Advances in understanding and management of retinopathy of prematurity

“…BDNF is important in ganglion cell maturation and is reduced in mice reared in the dark(58, 196). Several studies reported reduced circulating BDNF in extremely low birth weight infants, who developed ROP(77, 135), including in a study of extremely low birth weight infants enrolled through the US Neonatal Research Network. (163) Using genetically tested blood spots from infants in the same cohort, variants in the intronic region of the gene BDNF were found in association with severe ROP in extremely low birth weight infants.…”