【摘要】：背景： 白癜風(fēng)是一種常見(jiàn)的色素脫失性皮膚病，發(fā)病率呈逐年上升趨勢(shì)，皮損局部黑素細(xì)胞減少或消失是其色素脫失的主要原因。由于白癜風(fēng)發(fā)病的確切機(jī)制尚不清楚，目前仍缺乏有效的治療方法。近年來(lái)的研究發(fā)現(xiàn)，氧化應(yīng)激在誘發(fā)表皮黑素細(xì)胞破壞或功能障礙方面發(fā)揮關(guān)鍵作用。氧化應(yīng)激可通過(guò)產(chǎn)生大量的氧自由基來(lái)攻擊細(xì)胞，干擾其正常代謝、增殖和分化，并可能進(jìn)一步誘發(fā)機(jī)體自身免疫反應(yīng)，形成瀑布式效應(yīng)，造成表皮黑素細(xì)胞不可逆性損傷。與其它表皮細(xì)胞相比，白癜風(fēng)患者黑素細(xì)胞更易于受到氧化攻擊而發(fā)生損傷，然而這其中的原因和機(jī)制并不清楚。因此，闡明白癜風(fēng)患者黑素細(xì)胞易受到氧化損傷的原因和具體分子機(jī)制對(duì)于完善白癜風(fēng)氧化應(yīng)激發(fā)病機(jī)理、指導(dǎo)臨床治療具有重要的意義。 Nrf2-ARE通路是細(xì)胞對(duì)抗外源性刺激和氧化損傷的主要機(jī)制。Nrf2屬于“CNC”家族的亮氨酸拉鏈蛋白，它可與胞核內(nèi)的抗氧化反應(yīng)元件（ARE）的DNA序列結(jié)合，調(diào)控下游一系列II相解毒酶和抗氧化基因的表達(dá)。在無(wú)任何刺激的狀況下，Nrf2與胞漿伴侶蛋白Keap1相結(jié)合，處于相對(duì)抑制的狀態(tài)，并被鉚釘在胞漿中。當(dāng)處于氧化應(yīng)激條件時(shí)，Nrf2將與Keap1解偶聯(lián)并轉(zhuǎn)移入核，與核內(nèi)的抗氧化反應(yīng)元件結(jié)合，啟動(dòng)一系列II相解毒酶和抗氧化基因的表達(dá)。這些基因主要包括：血紅素氧合酶-1（HO-1）、NADP(H)醌氧化還原酶1（NQO1）、谷氨酸-半胱氨酸連接酶催化亞基（GCLC）和谷氨酸-半胱氨酸連接酶調(diào)節(jié)亞基（GCLM）。Nrf2-ARE信號(hào)通路及其下游基因已被證實(shí)在多種細(xì)胞、組織和器官抗氧化損傷中發(fā)揮重要作用。由此，我們提出如下的假說(shuō)：第一，Nrf2-ARE通路在保護(hù)黑素細(xì)胞抵抗氧化損傷中發(fā)揮重要作用；第二，白癜風(fēng)患者黑素細(xì)胞中Nrf2-ARE通路存在異常，導(dǎo)致其對(duì)氧化應(yīng)激更為敏感。 目的： 1.研究Nrf2-ARE通路及其下游分子在人黑素細(xì)胞中的表達(dá)情況，明確該通路在黑素細(xì)胞抗氧化應(yīng)激中的作用； 2.分析Nrf2-ARE通路在正常人和白癜風(fēng)患者黑素細(xì)胞中的表達(dá)及功能差異； 3.探討Nrf2-ARE通路及其下游分子在白癜風(fēng)患者黑素細(xì)胞中表達(dá)及功能差異的分子機(jī)制。 方法： 1.首先利用不同濃度的H_2O_2處理人黑素細(xì)胞PIG1，MTS實(shí)驗(yàn)檢測(cè)細(xì)胞活性，摸索建立體外黑素細(xì)胞氧化應(yīng)激模型的最佳條件； 2.在PIG1中通過(guò)轉(zhuǎn)染Nrf2干涉片段及過(guò)表達(dá)質(zhì)粒下調(diào)或者上調(diào)Nrf2的表達(dá)，氧化應(yīng)激下MTS和流式細(xì)胞術(shù)檢測(cè)細(xì)胞活性和凋亡情況。 3. H_2O_2預(yù)處理后，Real-time PCR檢測(cè)Nrf2下游主要的4個(gè)抗氧化基因（HO-1,NQO-1, GCLC和GCLM）表達(dá)水平，免疫細(xì)胞化學(xué)及Real-time PCR檢測(cè)原代黑素細(xì)胞中Nrf2及HO-1的表達(dá)情況。 4.分別利用MTS實(shí)驗(yàn)、Real-time PCR、免疫印跡、激光共聚焦顯微鏡、雙熒光素酶報(bào)告基因?qū)嶒?yàn)、流式細(xì)胞術(shù)以及酶聯(lián)免疫實(shí)驗(yàn)檢測(cè)氧化應(yīng)激下正常人及白癜風(fēng)患者黑素細(xì)胞活性、HO-1表達(dá)水平、Nrf2的核轉(zhuǎn)位情況、轉(zhuǎn)錄活性、細(xì)胞內(nèi)ROS和MDA水平以及SOD、GPx、CAT和GSH的含量。 5.用免疫組化法檢測(cè)白癜風(fēng)患者皮損處Nrf2、p-Nrf2和HO-1的表達(dá)分布模式，ELISA檢測(cè)患者血清中IL-2和HO-1表達(dá)水平。 6.應(yīng)用ATM干涉片段或抑制劑KU55933抑制ATM的表達(dá)后，Real Time-PCR和免疫印跡實(shí)驗(yàn)檢測(cè)Nrf2、HO-1和p-Nrf2的表達(dá)情況。H_2O_2預(yù)處理后，MTS實(shí)驗(yàn)、流式細(xì)胞術(shù)以及酶聯(lián)免疫實(shí)驗(yàn)檢測(cè)氧化應(yīng)激下黑素細(xì)胞活性、細(xì)胞內(nèi)ROS和MDA水平，免疫組化檢測(cè)白癜風(fēng)患者皮損處ATM和p-ATM表達(dá)分布模式。 結(jié)果： 1. H_2O_2可以濃度依賴性的方式誘導(dǎo)黑素細(xì)胞死亡，1.0mM H_2O_2處理24h是體外建立黑素細(xì)胞氧化應(yīng)激模型的最佳條件； 2. MTS實(shí)驗(yàn)及流式結(jié)果證實(shí)，下調(diào)Nrf2的表達(dá)可導(dǎo)致氧化應(yīng)激下細(xì)胞活性下降，增加細(xì)胞凋亡和壞死的比率；而上調(diào)Nrf2的表達(dá)則可提高細(xì)胞活性，顯著降低細(xì)胞凋亡的比率，說(shuō)明調(diào)節(jié)Nrf2-ARE通路可影響黑素細(xì)胞對(duì)氧化應(yīng)激的抵抗性； 3. Real-time PCR結(jié)果表明，H_2O_2可誘導(dǎo)Nrf2通路下游4個(gè)主要抗氧化基因表達(dá)升高，其中HO-1變化最顯著（升高了近5倍）。用HO-1抑制劑ZnPP預(yù)處理可增加過(guò)氧化氫對(duì)細(xì)胞的損傷，而用其激動(dòng)劑hemin預(yù)處理可提高細(xì)胞抗氧化能力，進(jìn)一步研究顯示，HO-1的表達(dá)水平與Nrf2的表達(dá)呈正相關(guān)，說(shuō)明HO-1可通過(guò)Nrf2通路保護(hù)黑素細(xì)胞避免氧化損傷； 4. MTS實(shí)驗(yàn)結(jié)果顯示，在未使用H_2O_2處理時(shí)，正常人和白癜風(fēng)患者黑素細(xì)胞活性無(wú)顯著差異，但在H_2O_2作用下，白癜風(fēng)患者黑素細(xì)胞活性較正常人相比顯著下降，說(shuō)明白癜風(fēng)患者黑素細(xì)胞對(duì)氧化應(yīng)激的敏感性更高； 5.激光共聚焦顯示，Nrf2在正常人黑素細(xì)胞（PIG1）中主要位于胞核，而在白癜風(fēng)患者黑素細(xì)胞（PIG3V）中則主要位于胞漿。在正常狀態(tài)下，PIG1細(xì)胞胞核中Nrf2的含量要高于PIG3V中，而胞漿中的含量則明顯低于PIG3V中；免疫印跡實(shí)驗(yàn)結(jié)果顯示，H_2O_2刺激后兩組黑素細(xì)胞胞核中Nrf2的含量均有所增加，但PIG3V細(xì)胞胞核中Nrf2的增加量顯著低于PIG1中；雙熒光素酶報(bào)告基因?qū)嶒?yàn)顯示，H_2O_2可在兩組黑素細(xì)胞中以時(shí)間依賴性的方式誘導(dǎo)Nrf2轉(zhuǎn)錄活性升高，而在PIG3V中Nrf2轉(zhuǎn)錄活性的升高幅度顯著低于PIG1中；進(jìn)一步研究顯示，在氧化應(yīng)激下，白癜風(fēng)患者黑素細(xì)胞中HO-1表達(dá)增高幅度顯著低于正常人黑素細(xì)胞中，說(shuō)明PIG3V中Nrf2存在激活障礙導(dǎo)致HO-1表達(dá)水平降低； 6.在PIG3V中上調(diào)Nrf2的表達(dá)可顯著減少氧化應(yīng)激下細(xì)胞死亡率，說(shuō)明激活Nrf2可降低PIG3V對(duì)氧化應(yīng)激的敏感性； 7.與PIG1相比，PIG3V細(xì)胞中ROS和MDA水平升高、SOD和GPx活性及總GSH和GSH含量降低，但是CAT活性在兩組細(xì)胞中無(wú)顯著差異，說(shuō)明PIG3V細(xì)胞中氧化-抗氧化失衡； 8.白癜風(fēng)患者皮損處表皮細(xì)胞中Nrf2、p-Nrf2和HO-1表達(dá)分布異常，細(xì)胞核內(nèi)Nrf2、p-Nrf2和HO-1含量減少，氧化應(yīng)激并未引起細(xì)胞核內(nèi)Nrf2、p-Nrf2和HO-1核轉(zhuǎn)位增加； 9.與健康對(duì)照相比，白癜風(fēng)患者血清中HO-1水平降低，而IL-2水平升高，同時(shí)發(fā)現(xiàn)血清HO-1水平與IL-2水平呈顯著負(fù)相關(guān)； 10.免疫組化結(jié)果表明，白癜風(fēng)患者皮損處表皮細(xì)胞中ATM表達(dá)降低，而p-ATM表達(dá)升高；在PIG1中下調(diào)ATM的表達(dá)可顯著抑制Nrf2、HO-1和p-Nrf2的表達(dá)，降低氧化應(yīng)激下黑素細(xì)胞活性，提高細(xì)胞內(nèi)ROS和MDA的水平，而對(duì)黑素合成及酪氨酸酶活性則無(wú)影響，提示ATM可通過(guò)作用于Nrf2通路影響細(xì)胞氧化應(yīng)激水平，ATM表達(dá)量降低可能是白癜風(fēng)患者黑素細(xì)胞中Nrf2通路存在激活障礙的原因。 結(jié)論： 通過(guò)本課題的研究，我們首次明確了Nrf2-ARE信號(hào)通路在黑素細(xì)胞抗氧化應(yīng)激中的重要作用，發(fā)現(xiàn)Nrf2激活障礙是白癜風(fēng)患者黑素細(xì)胞易于發(fā)生氧化損傷的原因，初步闡明了Nrf2存在激活障礙的分子機(jī)制，為進(jìn)一步認(rèn)識(shí)白癜風(fēng)中黑素細(xì)胞的損傷機(jī)制奠定了基礎(chǔ)。同時(shí)，本研究不僅豐富和完善了白癜風(fēng)氧化應(yīng)激發(fā)病機(jī)制，而且為臨床治療提供了新靶點(diǎn)。
[Abstract]:Background:
Vitiligo is a common depigmented skin disease. The incidence of vitiligo is increasing year by year. The decrease or disappearance of melanocytes is the main cause of depigmentation. Oxidative stress can attack cells by producing large amounts of oxygen free radicals, interfere with their normal metabolism, proliferation and differentiation, and may further induce the body's autoimmune response, forming a cascade effect, causing irreversible damage to epidermal melanocytes. Melanocytes in vitiligo patients are more susceptible to oxidative damage, but the reasons and mechanisms are not clear. Therefore, it is important to clarify the causes and specific molecular mechanisms of melanocytes in vitiligo patients susceptible to oxidative damage for improving the pathogenesis of oxidative stress and guiding clinical treatment.
Nrf2-ARE pathway is the main mechanism of cell resistance to exogenous stimuli and oxidative damage. Nrf2 belongs to the "CNC" family of leucine zipper proteins. It binds to the DNA sequence of the antioxidant response element (ARE) in the nucleus and regulates the expression of a series of downstream phase II detoxifying enzymes and antioxidant genes. When exposed to oxidative stress, Nrf2 uncouples with Keap1 and transfers to the nucleus, binds to antioxidant elements in the nucleus, and initiates the expression of a series of phase II detoxifying enzymes and antioxidant genes, including heme oxygenase-1 (HO-1). 1), NADP (H) quinone oxidoreductase 1 (NQO1), glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate-cysteine ligase regulatory subunit (GCLM). The Nrf2-ARE signaling pathway and its downstream genes have been demonstrated to play an important role in antioxidant damage in a variety of cells, tissues and organs. Nrf2-ARE pathway plays an important role in protecting melanocytes against oxidative damage. Secondly, the abnormal Nrf2-ARE pathway in melanocytes of vitiligo patients makes them more sensitive to oxidative stress.
Objective:
1. To study the expression of Nrf2-ARE pathway and its downstream molecules in human melanocytes, and to clarify the role of Nrf2-ARE pathway in antioxidant stress of melanocytes.
2. To analyze the expression and function of Nrf2-ARE pathway in melanocytes of normal subjects and vitiligo patients.
3. To investigate the expression and functional differences of Nrf2-ARE pathway and its downstream molecules in melanocytes of vitiligo patients.
Method:
1. Firstly, human melanocyte PIG1 was treated with different concentrations of H_2O_2. MTS assay was used to detect the cell activity and explore the best conditions for establishing melanocyte oxidative stress model in vitro.
2. The expression of Nrf2 was down-regulated or up-regulated by transfection of Nrf2 interference fragment and over-expression plasmid in PIG1, and the cell viability and apoptosis were detected by MTS and flow cytometry under oxidative stress.
3. After H_2O_2 pretreatment, the expression levels of four major antioxidant genes (HO-1, NQO-1, GCLC and GCLM) downstream of Nrf2 were detected by Real-time PCR. The expression of Nrf2 and HO-1 in primary melanocytes was detected by immunocytochemistry and Real-time PCR.
4. MTS assay, Real-time PCR, immunoblotting, confocal laser microscopy, double luciferase reporter gene assay, flow cytometry and enzyme-linked immunoassay were used to detect melanocyte activity, HO-1 expression level, Nrf2 nuclear translocation, transcriptional activity, intracellular ROS and MDA levels in normal persons and vitiligo patients under oxidative stress, respectively. The contents of SOD, GPx, CAT and GSH.
5. The expression patterns of Nrf2, p-Nrf2 and HO-1 in the lesions of vitiligo patients were detected by immunohistochemistry, and the expression levels of IL-2 and HO-1 in serum were detected by ELISA.
6. The expression of Nrf2, HO-1 and p-Nrf2 was detected by Real Time-PCR and Western blotting after ATM interference fragment or inhibitor KU55933 was used to inhibit the expression of ATM. After pretreatment with H_2O_2, MTS, flow cytometry and enzyme-linked immunosorbent assay were used to detect the activity of melanocytes under oxidative stress, the levels of ROS and MDA in cells, and immunohistochemistry was used to detect vitiligo. The distribution pattern of ATM and p-ATM in skin lesions.
Result:
1. H_2O_2 can induce melanocyte death in a concentration-dependent manner. 24 h treatment with 1.0 mH_2O_2 is the best condition for establishing melanocyte oxidative stress model in vitro.
2. MTS assay and flow cytometry showed that down-regulation of Nrf2 expression could decrease cell viability and increase the rate of apoptosis and necrosis under oxidative stress, and up-regulation of Nrf2 expression could increase cell viability and significantly decrease the rate of apoptosis, suggesting that regulation of Nrf2-ARE pathway could affect the resistance of melanocytes to oxidative stress.
3. Real-time PCR results showed that H_2O_2 could induce the expression of four major antioxidant genes downstream of Nrf2 pathway to increase, and HO-1 had the most significant change (nearly five times increased). Pretreatment with ZnPP, an inhibitor of HO-1, could increase the damage of hydrogen peroxide to cells, while hemin, an agonist, could enhance the antioxidant capacity of cells. Further studies showed that HO-1 inhibitor could increase the antioxidant capacity of cells. The expression level of HO-1 was positively correlated with that of Nrf2, indicating that HO-1 could protect melanocytes from oxidative damage through Nrf2 pathway.
4. MTS results showed that there was no significant difference in melanocyte activity between normal and vitiligo patients without H_2O_2 treatment, but the activity of melanocyte in vitiligo patients was significantly lower than that in normal people under H_2O_2 treatment, indicating that melanocytes in vitiligo patients were more sensitive to oxidative stress.
5. Laser confocal focusing showed that Nrf2 was mainly located in the nucleus of normal human melanocytes (PIG1) and mainly in the cytoplasm of vitiligo melanocytes (PIG3V). Under normal conditions, the content of Nrf2 in the nucleus of PIG1 cells was higher than that of PIG3V, but the content of Nrf2 in the cytoplasm was lower than that of PIG3V. Immunoblotting results showed that H_2O_2 was mainly located in the cytoplasm of vitiligo melanocytes (PIG3V). After stimulation, the Nrf2 content in the nucleus of both groups increased, but the Nrf2 content in the nucleus of PIG3V cells was significantly lower than that in PIG1 cells; the double luciferase reporter gene experiment showed that H_2O_2 could induce Nrf2 transcriptional activity to increase in a time-dependent manner in both groups of melanocytes, while the Nrf2 transcriptional activity increased in PIG3V cells. Further studies showed that under oxidative stress, the increase of HO-1 expression in melanocytes of vitiligo patients was significantly lower than that in normal melanocytes, suggesting that the activation of Nrf2 in PIG3V may lead to the decrease of HO-1 expression.
6. Up-regulation of Nrf2 expression in PIG3V can significantly reduce cell mortality under oxidative stress, indicating that activation of Nrf2 can reduce the sensitivity of PIG3V to oxidative stress.
7. Compared with PIG1, ROS and MDA levels in PIG3V cells increased, SOD and GPx activities and total GSH and GSH contents decreased, but CAT activity was not significantly different between the two groups of cells, indicating the imbalance of oxidation-antioxidation in PIG3V cells.
8. The expression and distribution of Nrf2, p-Nrf2 and HO-1 were abnormal in epidermal cells of vitiligo patients. The contents of Nrf2, p-Nrf2 and HO-1 in nucleus were decreased. Oxidative stress did not induce the increase of Nrf2, p-Nrf2 and HO-1 translocation in nucleus.
9. Compared with healthy controls, the serum HO-1 level was lower, while the serum IL-2 level was higher in vitiligo patients, and the serum HO-1 level was negatively correlated with the serum IL-2 level.
10. Immunohistochemical results showed that ATM expression was decreased and p-ATM expression was increased in the epidermal cells of vitiligo patients; down-regulation of ATM expression in PIG1 significantly inhibited the expression of Nrf2, HO-1 and p-Nrf2, decreased the activity of melanocytes under oxidative stress, and increased the levels of ROS and MDA, but not in melanogenesis and tyrosinase activity. The results suggest that ATM can affect the level of oxidative stress by acting on Nrf2 pathway, and the decrease of ATM expression may be the reason for the inactivation of Nrf2 pathway in melanocytes of vitiligo patients.
Conclusion:
Through this study, we first clarified the important role of Nrf2-ARE signaling pathway in melanocyte antioxidant stress, and found that the inactivation of Nrf2 is the cause of melanocyte prone to oxidative damage in vitiligo patients, and preliminarily elucidated the molecular mechanism of Nrf2 activation disorder, in order to further understand melanocyte in vitiligo. At the same time, this study not only enriched and improved the mechanism of oxidative stress in vitiligo, but also provided a new target for clinical treatment.
【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2013
【分類號(hào)】：R758.41

【共引文獻(xiàn)】

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