Alveolar type II cells maintain bioenergetic homeostasis in hypoxia through metabolic and molecular adaptation
Alveolar type II cells maintain bioenergetic homeostasis in hypoxia through metabolic and molecular adaptation
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DOI：
10.1152/ajplung.00298.2013
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发表时间：
2014-05-01
影响因子：
4.9
通讯作者：
Baatz, John E.
中科院分区：
文献类型：
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作者：
Lottes, Robyn G.;Newton, Danforth A.;Baatz, John E.
虽然许多肺部疾病与缺氧，肺泡II型上皮（ATII）细胞损伤，和肺表面活性物质功能障碍，O-2限制的影响，必要的代谢途径，以维持细胞能量的ATII细胞尚未得到广泛的研究。本报告介绍了有针对性的检测结果，旨在确定特定的代谢过程，有助于能量稳态使用原代ATII细胞和模型ATII细胞系，小鼠肺上皮细胞15（MLE-15），培养在常氧和缺氧条件下。在常氧条件下培养的MLE表现出强大的O-2消耗率（OCR），与ATP产生和有限的细胞外乳酸产生相结合，表明ATP产生依赖于氧化磷酸化。药理解偶联呼吸增加OCR在常氧文化的基础水平的175%，表明显着备用呼吸能力。然而，当暴露于缺氧20小时时，基础O-2消耗下降到常氧率的60%，并且细胞仅维持常氧备用呼吸能力的约50%，表明线粒体功能受到抑制，尽管细胞内ATP水平保持在接近常氧水平。此外，虽然低氧暴露刺激糖原合成和存储在MLE-15，糖酵解速率（通过乳酸产生测量）没有显着增加的细胞，尽管增强了几种酶的表达与糖酵解。这些结果在很大程度上在鼠原发性ATII中重现，证明MLE-15适用于建模ATII代谢。ATII细胞在缺氧条件下维持ATP水平而不增强糖酵解的能力表明，这些细胞在保存ATP以维持O-2限制下的生物能量稳态方面非常有效。
Although many lung diseases are associated with hypoxia, alveolar type II epithelial (ATII) cell impairment, and pulmonary surfactant dysfunction, the effects of O-2 limitation on metabolic pathways necessary to maintain cellular energy in ATII cells have not been studied extensively. This report presents results of targeted assays aimed at identifying specific metabolic processes that contribute to energy homeostasis using primary ATII cells and a model ATII cell line, mouse lung epithelial 15 (MLE-15), cultured in normoxic and hypoxic conditions. MLEs cultured in normoxia demonstrated a robust O-2 consumption rate (OCR) coupled to ATP generation and limited extracellular lactate production, indicating reliance on oxidative phosphorylation for ATP production. Pharmacological uncoupling of respiration increased OCR in normoxic cultures to 175% of basal levels, indicating significant spare respiratory capacity. However, when exposed to hypoxia for 20 h, basal O-2 consumption fell to 60% of normoxic rates, and cells maintained only -50% of normoxic spare respiratory capacity, indicating suppression of mitochondrial function, although intracellular ATP levels remained at near normoxic levels. Moreover, while hypoxic exposure stimulated glycogen synthesis and storage in MLE-15, glycolytic rate (as measured by lactate generation) was not significantly increased in the cells, despite enhanced expression of several enzymes related to glycolysis. These results were largely recapitulated in murine primary ATII, demonstrating MLE-15 suitability for modeling ATII metabolism. The ability of ATII cells to maintain ATP levels in hypoxia without enhancing glycolysis suggests that these cells are exceptionally efficient at conserving ATP to maintain bioenergetic homeostasis under O-2 limitation.