利用冷光誘導型基因轉殖小鼠探討乳鐵蛋白於高濃度氧所誘發的系統性發炎反應之抑制作用

張雯惠

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利用冷光誘導型基因轉殖小鼠探討乳鐵蛋白於高濃度氧所誘發的系統性發炎反應之抑制作用

Anti-Inflammatory Effects of Lactoferrin on Hyperoxia-Induced Systemic Inflammatory Responses using NF-κB/luciferase Transgenic Mice

張雯惠 , Masters　　Advisor：陳全木　　

繁體中文

乳鐵蛋白；高濃度氧；活體影像系統； NF-κB-Luciferase基因轉殖鼠； lactoferrin ； hyperoxia ； IVIS ； NF-κB-Luciferase transgenic mice

Abstract │ Reference (78) │ Altmetrics

Abstract 〈TOP〉

高濃度氧在臨床上常被用來治療低血氧相關的症狀，經由充足的氧氣換率以維持呼吸系統及組織的正常運作，但因高氧環境在生物體內容易造成活性氧化物的產生，長期使用高濃度氧治療，容易因氧分子的不穩定而轉變成自由基，產生毒性代謝物，使患者病情惡化。在許多研究中已證實乳鐵蛋白有抗發炎、抗氧化及抗病毒等多功能特性，其是一種含鐵離子的醣蛋白，大多存在於哺乳動物的乳汁中，並能幫助生物體增強免疫能力，因此本試驗中將以乳鐵蛋白的餵食，探討其對高濃度氧損傷之防禦功效。本研究試驗材料為NF-κB-Luciferase基因轉殖鼠，其帶有luciferase冷光基因，隨著高濃度氧誘發NF-κB的活化，冷光基因的表現量亦隨之增加，經由體外注射的受質（luciferin），與冷光蛋白反應，利用活體影像系統（in vivo imaging system；IVIS），以非侵入性方式，即時觀察冷光激發表現。本試驗以同型合子之NF-κB-Luciferase（NF-κB-Luc+/+）基因轉殖鼠分為四組：（1）NF-κB-Luc+/++ water小鼠正常控制組、（2）NF-κB-Luc+/+小鼠+ water +高濃度氧72小時、（3）NF-κB-Luc+/+ 小鼠+150 mg/kg 乳鐵蛋白+高濃度氧72小時、與（4）NF-κB-Luc+/+ 小鼠+300 mg/kg 乳鐵蛋白+高濃度氧72小時（n ≥ 5）。NF-κB-Luciferase基因轉殖鼠在預先餵食乳鐵蛋白14天後，加以高濃度氧環境作用72小時，並以活體影像分析乳鐵蛋白的抗發炎效果。試驗結果發現，NF-κB-Luciferase基因轉殖鼠在高濃度氧誘發後，在活體影像中腎臟會有較高度的冷光表現，肺部也有明顯的冷光激發但較微弱，成功建立活體冷光模式，而預處理乳鐵蛋白的組別中，其肺部及腎臟的冷光基因表現均降低，在高濃度氧誘發調控路徑中，肺部及腎臟的活性氧化物（ROS）與p-MAPK含量有顯著性減緩（p < 0.01），而IκB裂解比例亦顯著降低，且體內的IL-6、IL-1β及TNF-α等發炎相關因子均明顯下降（p < 0.01），得知乳鐵蛋白的餵食確實能有效減少高濃度氧所造成的NF-κB活化，進而達到減緩發炎反應的發生。推測為乳鐵蛋白的餵食可經由小腸黏膜細胞之乳鐵蛋白受體，將乳鐵蛋白帶到肺部及腎臟組織，於細胞內或血流中減少ROS生成；此外，乳鐵蛋白中的三價鐵離子能穩定活性氧化物的活性，減少自由基對生物體的傷害，以及對於發炎反應的抑制功效，而在後續研究中，將持續探討與追蹤相關的發炎路徑，並運用腎臟高度冷光表現之特性，進行局部性發炎與抑制的試驗。

Parallel Abstract 〈TOP〉

Hyperoxia is used to cure hypoxemia in clinical symptoms, through oxygen supplementation to maintain adequate tissue and respiratory oxygenation. However, exposure to hyperoxia may produce reactive oxygen species (ROS) in vivo easily. Lactoferrin (LF) is an iron-binding glycoprotein found in mammal’s milk, and it can improve immunomodulatory effects. Additionally, many studies demonstrated that LF has a number of biological functions including anti-inflammatory, anti-oxidant, anti-viral effects, and so on. Since patients were treated with hyperoxia for a long term, ROS would exacerbate disease with toxic metabolites. Therefore, we investigated the anti-inflammatory effects of LF on hyperoxia-induced systemic inflammatory responses. The anti-inflammatory therapy model was using NF-κB/luciferase transgenic mice (Tg mice), which are carrying the luciferase gene under the control of NF-κB. When NF-κB was activated by hyperoxia, luciferase protein would show higher expression. Luciferase protein would response with liciferin from injection, and then used non-invasive in vivo imaging system (IVIS) to observe luminescence excitation performance immediately. The transgenic mice with homozygous NF-κB/luciferase (NF-κB-Luc+/+) genotype were randomly assigned to four groups for treatments (n ≥ 5): (1) NF-κB-Luc+/+ mice treated with water, (2) NF-κB-Luc+/+ mice treated with water and hyperoxia for 72 hours, (3) NF-κB-Luc+/+ mice treated with 150 mg/kg LF and hyperoxia for 72 hours, and (4) NF-κB-Luc+/+ mice treated with 300 mg/kg LF and hyperoxia for 72 hours. And NF-κB-Luc+/+ mice pre-treated LF or water daily for 14 days. We found that the highest expression of luciferase protein in hyperoxia-induced NF-κB-Luc+/+ Tg mice were detected in the kidney tissue, and also weaker expression in lung tissue by IVIS, indicating that we established the in vivo image model successfully. As Tg mice were treated with LF, the lower expression of luciferase were observed in lung and kidney, and the ROS and p-MAPK expression also decreased significantly（p < 0.01）under hyperoxia condition. The decayed ratio of IκB also was decreased significantly. Additionally, LF effectively decreased the expression of the inflammatory factors including IL-6, IL-1β, and TNF-α（p < 0.01）. Data suggested that LF decreased the activation of NF-κB and exerted an anti-inﬂammatory effect under the hyperoxia-induced injury. We speculated that LF could be absorbed through specific LF receptors of intestinal mucosal cells. And LF would be transported to lung and kidney to decrease the produce of ROS in intracellular or blood flow. Besides, LF with Iron ions could balance the ROS activities, decrease the injury from radicals and inhibit the inflammatory effect. In the following study, we will continue to investigate and track the inflammation pathway. Furthermore, using the characteristics of kidney with highly luciferase expression, test the inflammatory and suppress effect in the local tissue.

Reference ( 78 ) 〈TOP〉

Adlerova, L., Bartoskova, A. and Faldyna, M. (2008) Lactoferrin: a review Vet. Med. 53: 457-468.
連結：
Aggarwal, B.B., Vijayalekshmi, R.V. and Sung, B. (2009) Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin. Cancer Res. 15: 425-430.
連結：
Aisen, P. and Leibman, A. (1972) Lactoferrin and transferrin: a comparative study. Biochim. Biophys. Acta 257: 314-323.
連結：
Arduini, A., Stern, A., Storto, S., Belfiglio, M., Mancinelli, G., Scurti, R. and Federici, G. (1989) Effect of oxidative stress on membrane phospholipid and protein organization in human erythrocytes. Arch Biochem. Biophys. 273: 112-120.
連結：
Baldwin, A.S.Jr. (1996) The NF-kappa B and I kappa B proteins: new discoveries and insights. Annu. Rev. Immunol. 14: 649-683.
連結：

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