Signorelli Sara, Jennings Paul, Leonard Martin O, Pfaller Walter
Innsbruck Medical University, Division of Physiology, Department of Physiology and Medical Physics, Innsbruck, Austria.
Cell Physiol Biochem. 2010;25(1):135-44. doi: 10.1159/000272066. Epub 2009 Dec 22.
Under hypoxic conditions eukaryotic cells and tissues undergo adaptive responses involving glycolysis, angiogenesis, vasoconstriction and inflammation. The underlying molecular mechanisms are not yet fully elucidated and are most likely cell and tissue specific. In the lung, alveolar epithelial cells and microvascular endothelial cells are highly sensitive to hypoxia and together orchestrate a rapid and sustained adaptive response. We examined the effect of different oxygen tensions on cell viability, glucose metabolism, key transcription factors and signaling molecules, in alveolar epithelial cells (A549) and microvascular endothelial cells (HMEC-1). Both cell types tolerated hypoxia without detectable cell injury. Hypoxia induced glycolysis in both epithelial and microvascular endothelial cells, although A549 cells exhibited a higher rate of glucose consumption. The transcription factor CREB (cAMP response element binding protein) was activated with decreasing oxygen tensions in both cell types. This effect was again more marked in A549 cells, demonstrating epithelial cells to be more oxygen sensitive. Activating Transcription Factor 3 (ATF-3) was heavily induced by hypoxia in A549 cells but not in HMEC-1 cells. Both cell types exhibited hypoxia induced secretion of VEGF and IL-6. Secretion of the vasoconstrictor endothelin-1 (ET1) was increased by hypoxia in HMEC-1 cells but decreased in A549 cells. These data reveal that both cell types exhibit an adaptive response to hypoxia but alveolar epithelial cells are generally more sensitive. ET-1 was oppositely regulated by decreased oxygen tensions in the investigated cell types. The present study further elucidates the adaptive molecular mechanisms in pulmonary hypoxia and demonstrates cell specific responses.
在缺氧条件下，真核细胞和组织会经历涉及糖酵解、血管生成、血管收缩和炎症的适应性反应。其潜在的分子机制尚未完全阐明，很可能具有细胞和组织特异性。在肺中，肺泡上皮细胞和微血管内皮细胞对缺氧高度敏感，并共同协调快速而持续的适应性反应。我们研究了不同氧张力对肺泡上皮细胞（A549）和微血管内皮细胞（HMEC-1）的细胞活力、葡萄糖代谢、关键转录因子和信号分子的影响。两种细胞类型都能耐受缺氧，未检测到细胞损伤。缺氧诱导上皮细胞和微血管内皮细胞的糖酵解，尽管A549细胞的葡萄糖消耗率更高。转录因子CREB（cAMP反应元件结合蛋白）在两种细胞类型中均随着氧张力降低而被激活。这种效应在A549细胞中再次更为明显，表明上皮细胞对氧更敏感。缺氧在A549细胞中强烈诱导激活转录因子3（ATF-3），但在HMEC-1细胞中未诱导。两种细胞类型均表现出缺氧诱导的VEGF和IL-6分泌。缺氧使HMEC-1细胞中血管收缩剂内皮素-1（ET1）的分泌增加，但使A549细胞中ET1的分泌减少。这些数据表明，两种细胞类型均表现出对缺氧的适应性反应，但肺泡上皮细胞通常更敏感。在所研究的细胞类型中，ET-1受氧张力降低的调控相反。本研究进一步阐明了肺缺氧中的适应性分子机制，并证明了细胞特异性反应。
