Winthrop University Hospital, Mineola, NY, USA.
Division of Neonatology, Department of Pediatrics, John R Oishei Children's Hospital, University at Buffalo, 1001 5th Floor Main Street, Buffalo, NY, 14203, USA.
BMC Pulm Med. 2019 Jul 30;19(1):138. doi: 10.1186/s12890-019-0903-x.
Caffeine therapy for apnea of prematurity reduces the incidence of bronchopulmonary dysplasia (BPD) in premature neonates. Several mechanisms, including improvement in pulmonary mechanics underly beneficial effects of caffeine in BPD. As vascular development promotes alveologenesis, we hypothesized that caffeine might enhance angiogenesis in the lung, promoting lung growth, thereby attenuating BPD.
C57Bl/6 mice litters were randomized within 12 h of birth to room air (RA) or 95%O to receive caffeine (20 mg/kg/day) or placebo for 4 days and recovered in RA for 12wks. The lung mRNA and protein expression for hypoxia-inducible factors (HIF) and angiogenic genes performed on day 5. Lung morphometry and vascular remodeling assessed on inflation fixed lungs at 12wks.
Caffeine and hyperoxia in itself upregulate HIF-2α and vascular endothelial growth factor gene expression. Protein expression of HIF-2α and VEGFR1 were higher in hyperoxia/caffeine and angiopoietin-1 lower in hyperoxia. An increase in radial alveolar count, secondary septal count, and septal length with a decrease in mean linear intercept indicate an amelioration of hyperoxic lung injury by caffeine. An increase in vessel surface area and a significant reduction in smooth muscle thickness of the pulmonary arterioles may suggest a beneficial effect of caffeine on vascular remodeling in hyperoxia, especially in male mice.
Postnatal caffeine by modulating angiogenic gene expression early in lung development may restore the pulmonary microvasculature and alveolarization in adult lung.
咖啡因治疗早产儿呼吸暂停可降低早产儿支气管肺发育不良（BPD）的发生率。包括改善肺力学在内的几种机制是咖啡因对 BPD 有益作用的基础。由于血管发育促进肺泡发生，我们假设咖啡因可能增强肺中的血管生成，促进肺生长，从而减轻 BPD。
C57Bl/6 幼鼠在出生后 12 小时内随机分为空气（RA）或 95%O 组，以接受咖啡因（20mg/kg/天）或安慰剂治疗 4 天，并在 RA 中恢复 12 周。第 5 天对缺氧诱导因子（HIF）和血管生成基因的肺 mRNA 和蛋白表达进行检测。在 12 周时对充气固定肺进行肺形态计量学和血管重塑评估。
咖啡因和高氧本身可上调 HIF-2α 和血管内皮生长因子基因表达。高氧/咖啡因组中 HIF-2α 和 VEGFR1 的蛋白表达较高，而高氧组中的血管生成素-1 较低。径向肺泡计数、次级间隔计数和间隔长度的增加以及平均线性截距的减少表明咖啡因可改善高氧肺损伤。血管表面积的增加和肺小动脉平滑肌厚度的显著减少可能提示咖啡因对高氧状态下血管重塑具有有益作用，尤其是在雄性小鼠中。
出生后通过调节肺发育早期的血管生成基因表达，咖啡因可能恢复成年肺的肺微血管和肺泡化。
