Chronic lung disease in preterm lambs: effect of daily vitamin A treatment on alveolarization
Chronic lung disease in preterm lambs: effect of daily vitamin A treatment on alveolarization
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DOI：
10.1152/ajplung.00380.2009
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发表时间：
2010-07-01
影响因子：
4.9
通讯作者：
Bland, Richard D.
中科院分区：
文献类型：
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作者：
Albertine, Kurt H.;Dahl, Mar Janna;Bland, Richard D.
Albertine KH，Dahl MJ，冈萨雷斯LW，Wang Z，Metcalfe D，Hyde DM，Plopper CG，Starcher BC，Carlton DP，Bland RD.早产羔羊慢性肺病：每日维生素A治疗对肺泡形成的影响。美国生理学杂志肺细胞分子生理学299：L59-L72，2010年。首次发表于2010年4月9日; doi：10.1152/ajplung.00380.2009。新生儿慢性肺部疾病的特征在于肺泡和毛细血管的形成失败，以及基质弹性蛋白的过度沉积，这与使用富含O-2气体的长时间机械通气（MV）有关。维生素A补充剂改善了早产儿的呼吸结果，但关于维生素A治疗后肺部结构和分子表现的信息很少。我们假设，在不受产前类固醇治疗干扰的情况下，在长时间MV期间补充维生素A将改善肺泡继发性分隔，降低远端气室壁之间的间充质组织核心的厚度，并增加肺泡毛细血管生长。我们进一步假设，这些结构的进步将与未成熟肺实质中弹性蛋白原的调节表达和基质弹性蛋白、磷酸化Smad 2（pSmad 2）、裂解的半胱天冬酶3、增殖细胞核抗原（PCNA）、VEGF、VEGF-R2和中期因子的沉积相关。8只早产羔羊（妊娠125天，足月与150天相似）通过MV管理3周：4只从出生时开始每日肌内注射Aquasol A（维生素A）5，000 IU/kg; 4只仅接受溶媒。死后肺分析包括定量RT-PCR和原位杂交，免疫印迹和免疫组织化学，形态计量学和体视学。每日补充维生素A可增加肺泡继发性分隔，减少远端气室壁间充质组织核心的厚度，并增加肺泡毛细血管的生长。相关的分子变化是弹性蛋白原mRNA表达减少，基质弹性蛋白沉积，pSmad 2和PCNA蛋白定位在远端气隙壁的间充质组织核心。另一方面，VEGF、VEGF-R2、中期因子和切割的半胱天冬酶3的mRNA表达和蛋白丰度增加。我们的结论是，维生素A治疗部分改善肺发育的慢性通气早产儿通过调节表达的弹性蛋白原，沉积的弹性蛋白，血管生长因子的表达。
Albertine KH, Dahl MJ, Gonzales LW, Wang Z, Metcalfe D, Hyde DM, Plopper CG, Starcher BC, Carlton DP, Bland RD. Chronic lung disease in preterm lambs: effect of daily vitamin A treatment on alveolarization. Am J Physiol Lung Cell Mol Physiol 299: L59-L72, 2010. First published April 9, 2010; doi:10.1152/ajplung.00380.2009.-Neonatal chronic lung disease is characterized by failed formation of alveoli and capillaries, and excessive deposition of matrix elastin, which are linked to lengthy mechanical ventilation (MV) with O-2-rich gas. Vitamin A supplementation has improved respiratory outcome of premature infants, but there is little information about the structural and molecular manifestations in the lung that occur with vitamin A treatment. We hypothesized that vitamin A supplementation during prolonged MV, without confounding by antenatal steroid treatment, would improve alveolar secondary septation, decrease thickness of the mesenchymal tissue cores between distal air space walls, and increase alveolar capillary growth. We further hypothesized that these structural advancements would be associated with modulated expression of tropoelastin and deposition of matrix elastin, phosphorylated Smad2 (pSmad2), cleaved caspase 3, proliferating cell nuclear antigen (PCNA), VEGF, VEGF-R2, and midkine in the parenchyma of the immature lung. Eight preterm lambs (125 days' gestation, term similar to 150 days) were managed by MV for 3 wk: four were treated with daily intramuscular Aquasol A (vitamin A), 5,000 IU/kg, starting at birth; four received vehicle alone. Postmortem lung assays included quantitative RT-PCR and in situ hybridization, immunoblot and immunohistochemistry, and morphometry and stereology. Daily vitamin A supplementation increased alveolar secondary septation, decreased thickness of the mesenchymal tissue cores between the distal air space walls, and increased alveolar capillary growth. Associated molecular changes were less tropoelastin mRNA expression, matrix elastin deposition, pSmad2, and PCNA protein localization in the mesenchymal tissue core of the distal air space walls. On the other hand, mRNA expression and protein abundance of VEGF, VEGF-R2, midkine, and cleaved caspase 3 were increased. We conclude that vitamin A treatment partially improves lung development in chronically ventilated preterm neonates by modulating expression of tropoelastin, deposition of elastin, and expression of vascular growth factors.