Oxygen-induced metabolic changes and transdifferentiation in immature fetal rat lung lipofibroblasts
Oxygen-induced metabolic changes and transdifferentiation in immature fetal rat lung lipofibroblasts
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DOI：
10.1016/s1096-7192(02)00140-3
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发表时间：
2002-11-01
影响因子：
3.8
通讯作者：
Rehan, VK
中科院分区：
文献类型：
--
作者：
Boros, LG;Torday, JS;Rehan, VK
早产儿缺乏足够的表面活性剂产生，通常需要氧气支持以实现充足的氧合。长期吸氧会导致支气管肺发育不良 (BPD)，这是一种以肺泡化和肌成纤维细胞增殖减弱为特征的疾病过程。在本研究中，我们研究了从未成熟（d18）和近期（d21）胎鼠肺中分离出的培养成纤维细胞对常氧（21％）和高氧（95％）暴露的反应的代谢适应性变化。我们使用[1,2-C-13(2)]D-葡萄糖示踪剂和气相色谱/质谱来表征核酸核糖、乳酸和棕榈酸合成途径之间的葡萄糖碳重新分配，并使用逆转录酶-聚合酶链反应来评估高氧暴露反应下的脂肪分化相关蛋白（ADRP）mRNA表达。每次传代时暴露于高氧都会导致 d18 成纤维细胞中 ADRP mRNA 表达下降（*，p < 0.05 对比 21% O-2）。这种传代依赖性转分化伴随着通过戊糖循环的非氧化步骤从葡萄糖合成核酸核糖的适度增加（9-20%）。相比之下，在高氧暴露的培养物中，d18成纤维细胞从葡萄糖从头合成棕榈酸酯的能力降低了85%以上，而d21成纤维细胞从头合成脂质的能力降低了32-38%，不太明显。从这些研究中可以得出以下结论：（1）对高氧具有成熟依赖性的敏感性； (2) ADRP 表达变化所证明的成纤维细胞的转分化伴随着影响从葡萄糖合成核糖酸的代谢酶的变化，以及 (3) 高氧特异性地抑制从葡萄糖的脂肪生成。因此，高氧诱导的代谢变化在肺成纤维细胞向肌成纤维细胞的转分化以及 BPD 的发病机制中发挥着关键作用。 (C)2002 爱思唯尔科学（美国）。版权所有。
Preterm infants lack adequate surfactant production and often require oxygen support for adequate oxygenation. Prolonged oxygen treatment leads to the development of bronchopulmonary dysplasia (BPD), a disease process characterized by the blunting of alveolarization and proliferation of myofibroblasts. In the present study, we investigated metabolic adaptive changes in cultured fibroblasts isolated from immature (d18) and near-term (d21), fetal rat lungs in response to normoxic (21%) and hyperoxic (95%) exposures. We used the [1,2-C-13(2)]D-glucose tracer and gas chromatography/mass spectrometry to characterize glucose carbon redistribution between the nucleic acid ribose, lactate, and palmitate synthetic pathways, and reverse transcriptase-polymerase chain reaction to assess adipose differentiation related protein (ADRP) mRNA expression in response to hyperoxic exposure. Exposure to hyperoxia at each passage caused decrease (*,p < 0.05 vs. 21% O-2) in ADRP mRNA expression in the d18 fibroblasts. This passage-dependent transdifferentiation is accompanied by a moderate (9-20%) increase in the synthesis of nucleic acid ribose from glucose through the non-oxidative steps of the pentose cycle. In contrast, d18 fibroblasts showed over an 85% decrease in the de novo synthesis of palmitate from glucose, while d21 fibroblasts showed a less pronounced 32-38% decrease in de novo lipid synthesis in hyperoxia-exposed cultures. It can be concluded from these studies that: (1) there is a maturation dependent sensitivity to hyperoxia; (2) transdifferentiation of flbroblast as demonstrated by changes in ADRP expression is accompanied by metabolic enzymes changes affecting ribose acid synthesis from glucose, and (3) hyperoxia specifically inhibits lipogenesis from glucose. Hyperoxia-induced metabolic changes thus play a key role in the transdifferentiation of lung fibroblasts to myofibroblasts and the pathogenesis of BPD. (C)2002 Elsevier Science (USA). All rights reserved.