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In vivo DNA damage and gene epigenetic changes during hyperoxia injury response to supplement oxygen therapy
|關鍵字:||Microarray;生物晶片;Methylation;Oxidative stress;Supplemental oxygen therapy;甲基化;氧化壓力;氧氣支持性療法||出版社:||生命科學系所||引用:||Antequera, F., and Bird, A. 1993. Number of CpG islands and genes in human and mouse. PNAS. 90: 11995-11999. Asami, S., Manabe, H., Miyake, J., Tsurudome, Y., Hirano, T., Yamaguchi, R., Itoh, H., and Kasai, H. 1997. Cigarette smoking induces an increase in oxidative DNA damage, 8-hydroxydeoxyguanosine, in a central site of the human lung. Carcinogenesis. 18: 1763-1766. Ballmaier, D., and Epe, B. 1995. Oxidative DNA damage induced by potassium bromate under cell-free conditions and in mammalian cells. Carcinogenesis. 16: 335-342. Barazzone, C., Horowitz, S., Donati, Y. R., Rodriguez, I., and Piguet, P. F. 1998. Oxygen toxicity in mouse lung: pathways to cell death. Am J Respir Cell Mol Biol. 19: 573-581. Barazzone, C., and White, C. W. 2000. Mechanisms of cell injury and death in hyperoxia: role of cytokines and Bcl-2 family proteins. 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Nucleic Acids Res. 20: 2287-2291.||摘要:||
臨床上，氧氣支持性療法常用於患有呼吸窘迫症候群的新生兒、小孩及成人上。氧氣支持性療法常使用大於90％氧氣，然而，高濃度氧氣會導致肺泡內皮細胞及第一型上皮細胞產生膨脹及細胞凋亡。目前仍不清楚高濃度氧氣如何使細胞受損及死亡，但值得注意的是高濃度氧氣會導致細胞內的活性含氧物質提高，如：氧化氫、超氧陰離子、過氧化氫，會導致氧化壓力的增加，進而對DNA、蛋白質及脂質造成危害。此篇研究中，我們建立了一套模擬高濃度氧氣導致損傷的動物模式，利用高效能液相層析串連質譜儀配合線上固相萃取技術，偵測高濃度氧氣環境中雌性CD-1 (ICR)小鼠的肺臟及肝臟內氧化壓力生物指標8-OHdG並利用CpG islands生物晶片來探討細胞對高氧環境的反應。發現8-OHdG會在起初暴露高濃度氧氣的二十四小時逐漸降低，至四十八小時降至最低量，突然地在七十二小時後顯著性的提高。由此可知，長時間暴露高濃度氧氣對細胞的損傷是複雜的反應過程，可能有許多基因的參與，晶片的技術將是一個有力的研究工具。我們使用CpG island生物晶片大範圍篩選小鼠啟動子區域，來研究細胞對此氧化壓力的反應，生物晶片可以同時分析7,300個CpG island甲基化程度且可專一地鎖定關於氧化壓力、發炎、細胞週期、細胞凋亡及細胞外修復的基因。我們發現一群異常甲基化的基因，如：Ogg1、細胞色素P450。Ogg1啟動子區域的CpG island甲基化程度在調節基因的表現扮演著重要的角色且Ogg1的活化可以移除8-OHdG。我們發現高濃度氧環境會影響不同時間序列上基因的表現及epigenetic改變，所以這些異常甲基化的CpG island可做為急性呼吸窘迫症候群的epigenetic markers。
Supplemental oxygen is a common clinical intervention for newborns, children, and adults with respiratory distress. Unfortunately, oxygen levels>90% cause extensive swelling and necrosis of alveolar endothelial and type I epithelial cells. It remains unclear how hyperoxia injures and kills cells. It is believed that cytotoxic reactive oxygen species (ROS) of hydrogen peroxide, superoxide anion, and hydroxyl radicals may causes damages of DNA, protein, and lipids. In this study, we established a hyperoxia-induced injury mice model associated with the quantitative determination of 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-OHdG) and the CpG islands microarray technology for studying the mechanisms behind this response. A rapid HPLC/MS/MS method coupled with a solid-phase extraction (SPE) system was used to determine 8-OHdG which is a potential marker of oxidative DNA damage by ROS in the lungs and livers of female CD-1 (ICR) mice. The mean level of 8-OHdG in 17 wild type mice were 24.75 ±1.75 8-OHdG per 106 dG in lungs and 25.68 ±2.79 8-OHdG per 106 dG in livers. Intriguingly, we found that the mean level of 8-OHdG was decreased in 24 and 48h post hyperoxia-treated both in lungs and livers but significant raised both in 72h. Clearly, the development of lung injury during prolonged oxygen exposure is a complex process, associated with changes in the expression of a number of genes important in the adaptive response to hyperoxia. Because it appears to be the balance between these factors, rather than any one factor in the development of lung injury during hyperoxia, array technology would provide a powerful tool. Accordingly, a large-scale mouse CpG island microarray was first used to study cellular responses to DNA damage in the differential expression of 7,300 genes over time, and then specifically looked at changes in the overall pattern of gene expression associated with oxidative stress, inflammation, cell cycle progression, apoptosis, and extracellular matrix repairing. We focused on changes occurring in the early stages of hyperoxic injury (24, 48, and 72h of oxygen exposure) to dissect gene methylation abnormality, such as Ogg1, Cytochrome P450 family (like Cyp7a1). 8-OHdG can be removed from damaged DNA by Ogg1, and the methylation of its CpG islands plays an important role in regulating gene expression. These CpG island loci those are potentially useful as epigenetic markers for predicting acute respiratory distress syndrome (ARDS). Consistent with this notion, hyperoxia environment stimulated time-dependent gene expression and epigenetic changes. In summary, prolonged high concentration of oxygen exposure damaging tissues is a complex process. This study provides a niche to understand the mechanisms for patients suffering from the toxic effects of supplemental oxygen therapy.
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