本文選題：Peroxiredoxin + 2　； 參考：《第二軍醫(yī)大學(xué)》2016年博士論文

【摘要】：背景:蛛網(wǎng)膜下腔出血(subarachnoid hemorrhage,SAH)是三大腦血管疾病之一,致死率、致殘率高,危害極大。SAH后蛛網(wǎng)膜下腔中常常留有大量紅細(xì)胞及其裂解產(chǎn)物,這些物質(zhì)可觸發(fā)一系列復(fù)雜的病理生理改變,包括腦水腫、氧化應(yīng)激、炎性反應(yīng)、細(xì)胞毒性作用等。而且,這些改變相互交錯(cuò)、一起作用,最終導(dǎo)致神經(jīng)細(xì)胞損傷、神經(jīng)功能障礙。Peroxiredoxin蛋白家族(peroxiredoxins,Prxs)是一類真核細(xì)胞中普遍存在的、起清除細(xì)胞內(nèi)過(guò)氧化物作用的抗氧化劑,同時(shí)介導(dǎo)調(diào)控過(guò)氧化氫水平的信號(hào)通路,并參與許多疾病的發(fā)生發(fā)展。進(jìn)一步研究發(fā)現(xiàn),Prxs出胞后失去原有的細(xì)胞保護(hù)功能,所扮演的角色轉(zhuǎn)變。例如,當(dāng)腦缺血卒中發(fā)生后,Prxs釋放至細(xì)胞外,啟動(dòng)嚴(yán)重的炎性反應(yīng),作用機(jī)制可能為通過(guò)Toll樣受體2(toll-like receptor 2,TLR2)與Toll樣受體4(toll-like receptor 4,TLR4)、激活核因子-κB(nuclear factor-κB,NF-κB)途徑啟動(dòng)損傷相關(guān)分子模式(damage-associated molecular pattern,DAMP)型炎性反應(yīng),導(dǎo)致神經(jīng)細(xì)胞損傷加劇,同時(shí)伴隨Prxs的進(jìn)一步釋放,促炎作用級(jí)聯(lián)放大,最終出現(xiàn)嚴(yán)重的損傷結(jié)果。胞外的Prxs表達(dá)水平也會(huì)相應(yīng)升高。而Peroxiredoxin 2(Prx2)作為Prxs家族六個(gè)成員之一,在紅細(xì)胞中蛋白含量居第三(僅次于血紅蛋白),在神經(jīng)元中也有廣泛表達(dá)。由于Prx2這一獨(dú)有的細(xì)胞分布特點(diǎn),其在SAH后EBI中可能會(huì)扮演極其重要的作用。理由是:紅細(xì)胞及其裂解產(chǎn)物是SAH后EBI的重要致傷因素,激活諸多損傷通路,而神經(jīng)元恰恰是這些損傷通路最終的靶細(xì)胞,因果交錯(cuò),作用疊加。因此,我們提出假設(shè):當(dāng)SAH發(fā)生后,蛛網(wǎng)膜下腔中紅細(xì)胞會(huì)因衰老或腫脹等因素逐漸破裂、釋放出Prx2;腦組織中神經(jīng)元因缺血、炎性反應(yīng)等因素出現(xiàn)損傷、壞死也會(huì)釋放出Prx2,導(dǎo)致腦脊液、腦皮層間質(zhì)中Prx2(即胞外Prx2)表達(dá)異常升高。-2-這些胞外prx2除了可能會(huì)直接導(dǎo)致神經(jīng)細(xì)胞損傷外,還可能會(huì)啟動(dòng)、并介導(dǎo)damp型炎性反應(yīng),加劇神經(jīng)元進(jìn)一步損傷,并伴隨prx2進(jìn)一步釋放,作用級(jí)聯(lián)放大,最終在sah后早期腦損傷中扮演極其重要的角色。方法:本課題首先運(yùn)用western-blotting技術(shù)觀察prx2在紅細(xì)胞中表達(dá)情況,再運(yùn)用免疫熒光技術(shù)分別從體內(nèi)、體外觀察prx2在各種腦細(xì)胞中分布,驗(yàn)證腦組織中prx2是否僅在神經(jīng)元上表達(dá)。隨后,采用兔枕大池一次注血方法建立大動(dòng)物實(shí)驗(yàn)性蛛網(wǎng)膜下腔出血模型,用western-blotting、酶聯(lián)免疫吸附實(shí)驗(yàn)(enzyme-linkedimmunosorbentassay,elisa)技術(shù)檢測(cè)紅細(xì)胞裂解液組與紅細(xì)胞懸液組、對(duì)照組中腦組織中prx2與腦脊液(cerebrospinalfluid,csf)中prx2、炎性因子(il-6、tnf-α)的含量,用免疫組織化學(xué)、nissl染色、he染色等技術(shù)觀察早期腦損傷及基底動(dòng)脈痙攣情況,初步得出胞外prx2可能參與早期腦損傷作用中。其次,分別建立sah體內(nèi)及體外模型,運(yùn)用western-blotting、real-timepcr等技術(shù)觀察sah后組織、原代神經(jīng)元及培養(yǎng)基中prx2在各個(gè)時(shí)程表達(dá)水平的變化,以驗(yàn)證sah后神經(jīng)元中prx2表達(dá)水平是否上升及被釋放至胞外。然后,運(yùn)用western-blotting、elisa及細(xì)胞活性檢測(cè)(cck8)等技術(shù)對(duì)胞外prx2對(duì)小膠質(zhì)細(xì)胞(bv2)的激活(tlr4、myd88及nf-κb表達(dá)上調(diào))、炎性因子白介素6(interleukin-6,il-6)、腫瘤壞死因子α(tumornecrosisfactor-α,tnf-α)的釋放及對(duì)原代神經(jīng)元的損傷等作用進(jìn)一步研究,闡述胞外prx2在實(shí)驗(yàn)性sah后早期腦損傷的作用機(jī)制。最后,回歸臨床,收集行髖關(guān)節(jié)置換術(shù)及sah患者的csf,將csf濃縮50倍后用于western-blotting觀察prx2的表達(dá),然后分析csf中prx2水平與hunt-hess分級(jí)的關(guān)系。結(jié)果:體內(nèi)及體外實(shí)驗(yàn)結(jié)果均表明:prx2在腦組織中僅神經(jīng)元廣泛表達(dá),并在紅細(xì)胞中含量豐富。sah后蛛網(wǎng)膜下腔中的紅細(xì)胞裂解、其胞內(nèi)prx2將進(jìn)入csf中,而神經(jīng)元中Prx2的m RNA水平早期迅速上調(diào)、蛋白表達(dá)隨后也明顯上升,隨著神經(jīng)元損傷、死亡、其胞內(nèi)Prx2也被釋放進(jìn)入培養(yǎng)基中,這兩者為胞外Prx2的來(lái)源。兔枕大池注射紅細(xì)胞裂解液實(shí)驗(yàn)顯示胞外Prx2表達(dá)與炎性因子含量正相關(guān),并可能參與早期腦損傷作用中。隨后進(jìn)一步研究發(fā)現(xiàn),胞外Prx2既可以直接促進(jìn)神經(jīng)元死亡、凋亡外,也可以通過(guò)激活TLR4/NF-κB通路、促進(jìn)炎性因子釋放,明顯加劇神經(jīng)元損傷,后者作用更為明顯。最后,臨床實(shí)驗(yàn)表明SAH后第3天患者CSF中Prx2含量升高,并與Hunt-Hess分級(jí)呈正相關(guān)。結(jié)論:本課題通過(guò)體內(nèi)、體外實(shí)驗(yàn)再次證實(shí):Prx2在腦組織中僅神經(jīng)元廣泛表達(dá),并在紅細(xì)胞中含量豐富。SAH后胞外Prx2含量上升,除直接促進(jìn)神經(jīng)元死亡外,更為重要的是通過(guò)激活TLR4/NF-κB通路、促進(jìn)炎性因子釋放,進(jìn)一步加劇神經(jīng)元損傷。在臨床上,CSF中Prx2含量也可作為SAH患者病情判斷及預(yù)后分析的可靠標(biāo)志物。本課題的發(fā)現(xiàn)對(duì)SAH后早期腦損傷的復(fù)雜機(jī)制做了進(jìn)一步地補(bǔ)充、完善,同樣也提示通過(guò)干預(yù)蛛網(wǎng)膜下腔中紅細(xì)胞的裂解及胞外Prx2信號(hào)通路可能會(huì)提高SAH患者的治療效果。
[Abstract]:Background: subarachnoid hemorrhage (subarachnoid hemorrhage, SAH) is one of the three cerebrovascular diseases, with high mortality and high disability rate. A large number of red cells and their cracking products are often left in the subarachnoid space after severe.SAH. These substances can trigger a series of complicated pathophysiological changes, including brain edema, oxidative stress, inflammatory reaction, and fine effects. Cytotoxicity, etc., and these changes interlace, interact together, and eventually lead to nerve cell damage. The.Peroxiredoxin protein family (peroxiredoxins, Prxs) is a common type of eukaryotic cells, which act as antioxidants to remove the action of intracellular peroxides and mediate signals that regulate the level of hydrogen peroxide. The pathway, and participation in the development of many diseases. Further studies have found that Prxs exocytosis loses its original cell protection function and plays a role change. For example, when cerebral ischemic stroke occurs, Prxs releases to the extracellular and starts a serious inflammatory response. The mechanism can be achieved through Toll like receptor 2 (Toll-like receptor 2, TLR2) and Toll Like receptor 4 (Toll-like receptor 4, TLR4), the activation of nuclear factor kappa B (nuclear factor- kappa B, NF- kappa B) pathway activates the damage related molecular model (damage-associated molecular pattern,) type inflammatory response, which leads to the aggravation of nerve cell damage, accompanied by the progressive release, the enlargement of the proinflammatory cascade, and the eventual severe damage junction. Peroxiredoxin 2 (Prx2), one of the six members of the Prxs family, is third (second only to hemoglobin) in red blood cells, and is also widely expressed in neurons. Because of Prx2, a unique cell distribution point, it may play an extremely important role in EBI after SAH. The reason is that red blood cells and their cracking products are important injury factors of EBI after SAH, activating many damage pathways, and neurons are the final target cells of these damage pathways, which are interlaced and superimposed. Therefore, we hypothesized that when SAH occurs, the red cells in the subarachnoid cavity are gradually broken down due to aging or swelling and other factors. Prx2; neurons in brain tissue are damaged by ischemia, inflammatory reaction and other factors, and necrosis will release Prx2, causing cerebrospinal fluid, Prx2 (i.e., extracellular Prx2) expression abnormal increase of.-2- these extracellular Prx2 may also initiate, but may also initiate the damp type inflammatory reaction and aggravate the nerve. Further damage, accompanied by further release of Prx2, the role of cascade amplification, and eventually play an important role in the early brain damage after SAH. Methods: this subject first used Western-blotting technology to observe the expression of Prx2 in red blood cells, and then using immunofluorescence technique to observe the contents of Prx2 in various brain cells from the body and in vitro. Prx2 was used to verify whether the brain tissue was only expressed on the neurons. Then, the experimental subarachnoid hemorrhage model of large animals was established by the single injection of blood in the big pool of the rabbit pillow. Western-blotting, enzyme-linkedimmunosorbentassay (ELISA) technique was used to detect the erythrocyte lysate group and the red cell suspension group, and the control group was used as the control group. The content of Prx2 and inflammatory factors (IL-6, tnf- alpha) in Prx2 and cerebrospinalfluid (CSF) in the middle brain tissue. The early brain injury and basilar artery spasm were observed by immunohistochemistry, Nissl staining, he staining and other techniques. It was preliminarily concluded that extracellular Prx2 might be involved in early brain injury. Secondly, the internal and external models of SAH were established respectively. Western-blotting, real-timepcr and other techniques were used to observe the changes in the expression level of Prx2 in the tissues, the primary neurons and the culture medium in each time history, in order to verify whether the Prx2 expression level in the SAH neurons increased and was released to the extracellular. Then, the Western-blotting, ELISA and cell activity detection (CCK8) and other techniques were applied to the extracellular Prx2. The activation of microglia (BV2) (TLR4, MyD88 and nf- kappa B expression), the release of inflammatory factor interleukins 6 (interleukin-6, IL-6), tumor necrosis factor alpha (tumornecrosisfactor- a, tnf- alpha) and the damage to primary neurons, the mechanism of the action of extracellular Prx2 in the early stage of brain injury after experimental SAH was explained. Return to clinical, collect the hip arthroplasty and the CSF of SAH patients, concentrate 50 times the concentration of CSF in Western-blotting to observe the expression of Prx2, and then analyze the relationship between Prx2 level and Hunt-Hess grading in CSF. Results: in vivo and in vitro experimental results all show that Prx2 is widely expressed in the brain tissue, and the content of.Sah is rich in red cells after.Sah. The erythrocyte lysis in the subarachnoid space, its intracellular Prx2 will enter into CSF, and the m RNA level of Prx2 in the neuron is rapidly up-regulated at the early stage, and the protein expression then increases obviously. With the neuron damage, the intracellular Prx2 is released into the culture medium, both of which are the source of the extracellular Prx2. The rabbit pillow big pool is injected with the erythrocyte lysate experiment. The expression of extracellular Prx2 is positively related to the content of inflammatory factors and may be involved in early brain damage. Further studies have found that extracellular Prx2 can directly promote neuronal death and apoptosis, and can also stimulate the release of inflammatory factors by activating the TLR4/NF- kappa B pathway, which obviously aggravates the neuronal damage. The latter is more obvious. After the clinical experiment, the clinical experiment showed that the content of Prx2 in CSF increased in third days after SAH and was positively correlated with the Hunt-Hess classification. Conclusion: the subject through in vivo, in vitro experiments again confirmed that Prx2 was only widely expressed in the brain tissue, and the content of Prx2 increased after the rich.SAH in the red cells, which was more serious in addition to the direct promotion of neuronal death. It is necessary to activate the TLR4/NF- kappa B pathway to promote the release of inflammatory factors and further aggravate the neuron damage. In clinical, the Prx2 content in CSF can also be used as a reliable marker for the diagnosis and prognosis of SAH patients. The findings of this study further complement and improve the complex mechanism of early brain injury after SAH. Interfering with the lysis of erythrocytes and the extracellular Prx2 signaling pathway in the subarachnoid space may improve the therapeutic effect of SAH patients.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R743.35

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5 指導(dǎo)專家 第三軍醫(yī)大學(xué)大坪醫(yī)院腦血管病醫(yī)院第三科主任 蔣曉江 記者 李艷 通訊員 朱廣平;蛛網(wǎng)膜下腔出血 保守治療風(fēng)險(xiǎn)高[N];醫(yī)藥導(dǎo)報(bào);2006年

6 王惠英 臧海玉;精神異常者要警惕蛛網(wǎng)膜下腔出血[N];中國(guó)中醫(yī)藥報(bào);2004年

7 衣曉峰　王慧穎 記者 韓雪;蛛網(wǎng)膜下腔出血研究獲突破[N];黑龍江日?qǐng)?bào);2011年

8 霍濱;蛛網(wǎng)膜下腔出血也可表現(xiàn)為癲癇發(fā)作[N];家庭醫(yī)生報(bào);2005年

9 趙強(qiáng) 楊聲瑞;蛛網(wǎng)膜下腔出血治療技術(shù)創(chuàng)新[N];中國(guó)醫(yī)藥報(bào);2005年

10 ;蛛網(wǎng)膜下腔出血急救方法[N];農(nóng)村醫(yī)藥報(bào)（漢）;2008年

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1 王濤;1.半胱胺對(duì)大鼠蛛網(wǎng)膜下腔出血后早期腦損傷的保護(hù)作用 2.鴉膽子苦素A與酮康唑?qū)?xì)胞色素P450(CYP)3A4的潛在抑制作用對(duì)比研究[D];山東大學(xué);2015年

2 趙冬;縫隙連接蛋白、微動(dòng)脈膜電位和內(nèi)質(zhì)網(wǎng)應(yīng)激通路與蛛網(wǎng)膜下腔出血后遲發(fā)性腦缺血關(guān)系的研究[D];華中科技大學(xué);2015年

3 孫青;高遷移率族蛋白1在蛛網(wǎng)膜下腔出血后早期腦損傷中的作用研究[D];南京大學(xué);2014年

4 莊宗;氫氣在兔蛛網(wǎng)膜下腔出血后早期的腦保護(hù)作用及機(jī)制研究[D];南京大學(xué);2014年

5 崔永華;硫化氫對(duì)蛛網(wǎng)膜下腔出血后早期腦損傷的影響及其機(jī)制的研究[D];蘇州大學(xué);2016年

6 黨寶齊;Cyclophilin A/CD147信號(hào)通路在蛛網(wǎng)膜下腔出血后早期腦損傷中的作用及其分子機(jī)制研究[D];蘇州大學(xué);2016年

7 劉昊;高壓氧對(duì)蛛網(wǎng)膜下腔出血大鼠早期腦損傷的作用機(jī)制研究[D];南方醫(yī)科大學(xué);2016年

8 莫杭波;頭孢曲松在蛛網(wǎng)膜下腔出血早期腦損傷中的保護(hù)作用及機(jī)制研究[D];浙江大學(xué);2016年

9 錢聰;SIRT1在大鼠蛛網(wǎng)膜下腔出血后早期腦損傷模型的神經(jīng)保護(hù)作用及機(jī)制研究[D];浙江大學(xué);2016年

10 黃巍;SIRT3在實(shí)驗(yàn)性蛛網(wǎng)膜下腔出血后早期腦損傷中的作用及分子機(jī)制研究[D];第二軍醫(yī)大學(xué);2016年

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2 陳揚(yáng);實(shí)驗(yàn)性蛛網(wǎng)膜下腔出血后海馬微血管密度及側(cè)腦室脈絡(luò)叢的變化[D];河北聯(lián)合大學(xué);2014年

3 徐祥;mTOR信號(hào)通路在蛛網(wǎng)膜下腔出血后早期腦損傷中的作用及機(jī)制研究[D];蘇州大學(xué);2015年

4 陳軍輝;阿托伐他汀對(duì)兔蛛網(wǎng)膜下腔出血后早期腦損傷的保護(hù)作用及其機(jī)制的實(shí)驗(yàn)研究[D];安徽醫(yī)科大學(xué);2015年

5 李波;磷酯酰膽堿特異性磷脂酶C在蛛網(wǎng)膜下腔出血引起的早期腦損傷中的作用及其機(jī)制研究[D];蘇州大學(xué);2015年

6 何昊沅;腦動(dòng)脈血管壁在兔蛛網(wǎng)膜下腔出血后結(jié)構(gòu)性重建的研究[D];安徽醫(yī)科大學(xué);2015年

7 鄒敏剛;MMP-9、ZO-1及Cx43在蛛網(wǎng)膜下腔出血后腦血管痙攣機(jī)制中的相關(guān)研究[D];南昌大學(xué)醫(yī)學(xué)院;2015年

8 高安舉;Neurexin-1β及Neuroligin-1與蛛網(wǎng)膜下腔出血后認(rèn)知功能損害的關(guān)系研究[D];蘇州大學(xué);2015年

9 任寶鑫;Wnt3a在大鼠蛛網(wǎng)膜下腔出血后早期腦損傷中對(duì)神經(jīng)細(xì)胞自噬和凋亡的影響[D];山東大學(xué);2015年

10 黃立添;IL-33在蛛網(wǎng)膜下腔出血后大鼠腦組織中的表達(dá)及在炎癥反應(yīng)中的可能作用[D];南方醫(yī)科大學(xué);2015年

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