Prolonged mechanical ventilation with air induces apoptosis and causes failure of alveolar septation and angiogenesis in lungs of newborn mice
Prolonged mechanical ventilation with air induces apoptosis and causes failure of alveolar septation and angiogenesis in lungs of newborn mice
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DOI：
10.1152/ajplung.00251.2009
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发表时间：
2010-01-01
影响因子：
4.9
通讯作者：
Bland, Richard D.
中科院分区：
文献类型：
--
作者：
Mokres, Lucia M.;Parai, Kakoli;Bland, Richard D.
首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容长时间空气机械通气可诱导新生小鼠肺组织细胞凋亡，导致肺泡间隔和血管生成障碍。Am J Physiol肺细胞Mol Physiol 298：L23-L35,2010。2009年10月23日首次出版；DOI：10.1152/ajpeng.00251.2009。-肺间隔和血管生成缺陷是新生儿慢性肺病的典型特征，通常是由于发育中的肺长期暴露在机械通风(MV)和高氧环境下造成的。先前的研究表明，与正常对照组相比，CLD早产儿和羔羊肺组织中的肺泡和微血管减少，血管内皮生长因子减少，转化生长因子-β信号转导增加，弹性蛋白过多、分散。新生小鼠在40%O-2作用24小时后出现类似的肺结构异常，与血管内皮细胞生长因子信号转导受损、弹性蛋白生成失调和细胞凋亡增加有关。这些研究不能确定周期性拉伸与高氧在导致这些肺生长异常中的相对重要性。因此，我们研究了空气中持续24 h的MV对6天龄小鼠肺泡间隔(定量肺组织学)、血管生成[CD31定量免疫组织化学(IHC)、免疫印迹]、细胞凋亡[TdT介导的dUTP缺口末端标记(TUNEL)、活性caspase-3检测]、血管内皮生长因子信号[血管内皮生长因子-A、血管内皮生长因子受体1(VEGF-R1)、血管内皮生长因子-R2免疫印迹]、转化生长因子β[磷酸化Smad2(PSmad2)定量-免疫印迹]和弹性蛋白产生(原弹性蛋白免疫印迹、Hart‘s染色切片图像分析)的影响。与未换气对照组相比，机械通气组肺泡面积增加3倍，肺泡数目和内皮表面积减少50%，细胞凋亡率增加5倍，肺血管内皮生长因子-R2蛋白减少50%，pSmad2蛋白增加4倍，肺弹性蛋白增加50%，分布于肺泡壁而不是肺间隔。这项研究首次表明，在没有相关高氧的情况下，延长发育中肺的MV可以抑制肺泡间隔和血管生成，并增加细胞凋亡和肺弹性蛋白，这一发现可能反映了拉伸诱导的血管内皮生长因子和转化生长因子β信号的变化，如CLD报道的那样。
Mokres LM, Parai K, Hilgendorff A, Ertsey R, Alvira CM, Rabinovitch M, Bland RD. Prolonged mechanical ventilation with air induces apoptosis and causes failure of alveolar septation and angiogenesis in lungs of newborn mice. Am J Physiol Lung Cell Mol Physiol 298: L23-L35, 2010. First published October 23, 2009; doi: 10.1152/ajplung.00251.2009.-Defective lung septation and angiogenesis, quintessential features of neonatal chronic lung disease (CLD), typically result from lengthy exposure of developing lungs to mechanical ventilation (MV) and hyperoxia. Previous studies showed fewer alveoli and microvessels, with reduced VEGF and increased transforming growth factor-beta (TGF beta) signaling, and excess, scattered elastin in lungs of premature infants and lambs with CLD vs. normal controls. MV of newborn mice with 40% O-2 for 24 h yielded similar lung structural abnormalities linked to impaired VEGF signaling, dysregulated elastin production, and increased apoptosis. These studies could not determine the relative importance of cyclic stretch vs. hyperoxia in causing these lung growth abnormalities. We therefore studied the impact of MV for 24 h with air on alveolar septation ( quantitative lung histology), angiogenesis [CD31 quantitative-immunohistochemistry (IHC), immunoblots], apoptosis [TdT-mediated dUTP nick end labeling (TUNEL), active caspase-3 assays], VEGF signaling [VEGF-A, VEGF receptor 1 (VEGF-R1), VEGF-R2 immunoblots], TGF beta activation [phosphorylated Smad2 (pSmad2) quantitative-IHC], and elastin production (tropoelastin immunoblots, quantitative image analysis of Hart's stained sections) in lungs of 6-day-old mice. Compared with unventilated controls, MV caused a 3-fold increase in alveolar area, similar to 50% reduction in alveolar number and endothelial surface area, >5-fold increase in apoptosis, >50% decrease in lung VEGF-R2 protein, 4-fold increase of pSmad2 protein, and >50% increase in lung elastin, which was distributed throughout alveolar walls rather than at septal tips. This study is the first to show that prolonged MV of developing lungs, without associated hyperoxia, can inhibit alveolar septation and angiogenesis and increase apoptosis and lung elastin, findings that could reflect stretch- induced changes in VEGF and TGF beta signaling, as reported in CLD.