本文選題：寡核苷酸 + 炎性小體��； 參考：《山東大學(xué)》2016年博士論文

【摘要】：研究背景腦卒中是目前對(duì)人類危害最嚴(yán)重的疾病之一。腦卒中是高發(fā)病率、高致殘率、高復(fù)發(fā)率、高死亡率、高經(jīng)濟(jì)負(fù)擔(dān)的“五高”疾病。在我國(guó),腦卒中是位列第一的死亡原因。免疫炎癥在卒中的發(fā)生發(fā)展的病理發(fā)展過程中起重要作用。炎癥是機(jī)體對(duì)刺激做出的一種防御反應(yīng),在生物體內(nèi)起重要作用。當(dāng)受到刺激因子的刺激時(shí),會(huì)誘發(fā)炎癥反應(yīng),從而修復(fù)組織,抵抗損傷。炎癥也會(huì)對(duì)機(jī)體產(chǎn)生不良影響,導(dǎo)致免疫系統(tǒng)紊亂。已經(jīng)知道炎癥和免疫與卒中尤其是缺血性腦卒中的多種危險(xiǎn)因素相關(guān),包括高血壓、動(dòng)脈粥樣硬化、糖尿病、房顫、吸煙所致的血管損害等等。更為有趣的是腦血管病的事件導(dǎo)致了損傷相關(guān)的分子模式(damage associated molecular patterns, DAMPs)的釋放,從而增強(qiáng)了先天免疫反應(yīng),最后導(dǎo)致腦損害和有關(guān)的神經(jīng)功能的缺失。目前公認(rèn)的急性缺血性腦卒中的有效的治療方法是在有效的時(shí)間窗內(nèi)盡早恢復(fù)腦灌注,如臨床上應(yīng)用重組組織型纖溶酶原激活劑(recombinant tissue plasminogen activator, rTPA)進(jìn)行超早期靜脈溶栓,臨床效果好,但是卻受治療時(shí)間窗、病人的一般情況及溶栓后容易并發(fā)出血等的各種并發(fā)癥的多種因素的制約,所以只有大約不到20%的病人能獲益,盡早恢復(fù)腦灌注在臨床的實(shí)際治療中存在困難。尋求有效的腦保護(hù)治療成為多年研究的重點(diǎn)。幾十年來大量的研究者專注于的細(xì)胞保護(hù)作用機(jī)制的研究,使腦細(xì)胞在缺血缺氧應(yīng)激后仍能保持細(xì)胞內(nèi)穩(wěn)態(tài)的動(dòng)態(tài)平衡,從而保護(hù)腦細(xì)胞不被破壞。實(shí)驗(yàn)在動(dòng)物體內(nèi)均獲得很好的成效,但在臨床轉(zhuǎn)化研究中卻均失敗。盡管如此,在國(guó)際卒中組織的努力下,卒中的病理發(fā)展過程方面的研究仍有很大的進(jìn)步。炎性小體(Inflammasomes)是一種多蛋白復(fù)合體,作為先天免疫的一部分可以在應(yīng)激和感染等感受到外界信號(hào)刺激的情況下激活半胱天冬氨酸蛋白水解酶-1(caspase-1),從而產(chǎn)生白介素1β(IL-1β)和白介素18(IL-18)。Caspase-1和IL-1β增強(qiáng)炎癥反應(yīng)和細(xì)胞死亡,IL-1β在很多疾病包括腦缺血性損害過程中起重要作用,其機(jī)制尚未揭示。在卒中實(shí)驗(yàn)中,隨著腦缺血的發(fā)生,IL-1β的表達(dá)增多,而且多個(gè)實(shí)驗(yàn)證實(shí),阻止IL-1β的產(chǎn)生具有腦保護(hù)作用。值得注意的是人類的缺血性腦卒中血液和腦脊液中均可發(fā)現(xiàn)IL-1β的水平增高。在鼠模型中,腦缺血性損害后炎性小體相關(guān)蛋白水平增高,降低炎性小體相關(guān)蛋白水平可以減輕損害的程度。受損的細(xì)胞,包括神經(jīng)細(xì)胞可以釋放出三磷酸腺苷(ATP)、尿苷三磷酸(UTP),激活小膠質(zhì)細(xì)胞或巨噬細(xì)胞上的離子通道P2X7受體,從而導(dǎo)致炎癥因子前體的產(chǎn)生。Caspasel嵌合在大分子蛋-NLRP3上,在Caspasel的作用下,成熟的IL-1β、IL-18由其前體轉(zhuǎn)化而來。缺血損害以及細(xì)胞的死亡導(dǎo)致了DAMPs的形成。DAMPs包括高遷移率族蛋白1(HMGB1)、熱休克蛋白HSP60、A β,可以作用于細(xì)胞表面的Tool樣受體(TLR),從而使炎性前體的基因表達(dá)增多。細(xì)胞因子的產(chǎn)生及補(bǔ)體的形成引起了白細(xì)胞浸潤(rùn)的增加,擴(kuò)大了腦的損害,這樣能產(chǎn)生更多的DAMPs,進(jìn)一步加重?fù)p害。同時(shí)由損害細(xì)胞釋放的抗原也激活T細(xì)胞介導(dǎo)的適應(yīng)性的免疫。 這些近期的發(fā)展使得需要再評(píng)估炎癥和免疫在卒中病理生理過程中的作用。2009年諾貝爾獎(jiǎng)的獲得者發(fā)現(xiàn)了染色體末端的端粒帽端粒帽能保護(hù)染色體防止其融合、降解和重組等,為衰老和癌癥的研究奠定了基礎(chǔ)。哺乳動(dòng)物的端粒由TTAGGG堿基對(duì)組成,這些堿基對(duì)從死亡的宿主細(xì)胞中釋放并且能減輕引起組織損害的炎癥反應(yīng)。合成的寡核苷酸A151是由四個(gè)TTAGGG堿基對(duì)結(jié)合在硫代磷酸酯骨架上構(gòu)成。A151復(fù)制了端粒DNA調(diào)節(jié)炎癥反應(yīng)的能力,包括調(diào)節(jié)白介素6(IL-6)、白介素12(IL-12)、γ干擾素(IFNγ)、巨噬細(xì)胞炎癥蛋白2(MIP-2)和腫瘤壞死因子α(TNFα)的產(chǎn)生。A151作為一種的抗炎癥反應(yīng)制劑,其治療潛能已經(jīng)在關(guān)節(jié)炎、內(nèi)毒素休克、刀豆蛋白A誘導(dǎo)的暴發(fā)性肝炎、眼部炎癥、狼瘡腎炎、動(dòng)脈粥樣硬化和二氧化硅所致的肺部炎癥等動(dòng)物模型中得到證實(shí)。至關(guān)重要的是,硫代磷酸寡核苷酸的的藥效學(xué)和安全性已經(jīng)在多個(gè)臨床試驗(yàn)中得到證實(shí)。A151對(duì)腦缺血后的炎癥免疫反應(yīng)的影響以及對(duì)腦缺血是否具有保護(hù)作用目前尚無人研究,基于IL-1β在腦缺血性損害中的作用以及A151成功改進(jìn)多種疾病炎性因子的基礎(chǔ)上,如果A151能減輕腦缺血后的炎癥免疫反應(yīng),并對(duì)腦缺血損害具有保護(hù)作用,將為缺血性腦卒中的治療提供新的亮點(diǎn)。腦缺血損害時(shí),骨髓巨噬細(xì)胞和小膠質(zhì)細(xì)胞是IL-1β的主要來源。腦缺血后,除了血管周圍的巨噬細(xì)胞,單核細(xì)胞迅速滲入大腦也成為巨噬細(xì)胞。所以本實(shí)驗(yàn)選用骨髓巨噬細(xì)胞在細(xì)菌脂多糖(LPS)和糖氧剝奪(OGD)雙重處理來模擬腦內(nèi)缺血缺氧狀態(tài)。易卒中自發(fā)性高血壓大鼠(SHR-SP大鼠)生存期短,易發(fā)卒中,是研究腦卒中最為理想的動(dòng)物模型。本實(shí)驗(yàn)采用SHR-SP大鼠的永久性大腦中動(dòng)脈離斷手術(shù)模型進(jìn)行研究。本實(shí)驗(yàn)所應(yīng)用的A151及對(duì)照劑寡核苷酸C151(5'-TTCAAATTCAAATTCAAATTCAAA-3')由美國(guó)食品藥物管理局(FDA)生物制品評(píng)價(jià)和研究中心(CBER)提供。目的1.體外部分：將骨髓巨噬細(xì)胞予以LPS和OGD的雙重協(xié)同處理,以求模擬腦內(nèi)的缺血缺氧的環(huán)境,檢測(cè)A151在缺氧缺糖損害后的骨髓巨噬細(xì)胞的免疫炎癥反應(yīng)中的作用,能否減少炎性因子的釋放,減輕炎癥反應(yīng)從而并減輕細(xì)胞的損害。2.體內(nèi)部分：應(yīng)用SHR-SP大鼠的永久性大腦中動(dòng)脈離斷手術(shù)模型,將從動(dòng)物的行為、組織、免疫、基因等水平分別來觀察A151對(duì)發(fā)生卒中后的SHR-SP大鼠的炎性因子的影響以及對(duì)腦組織的保護(hù)作用,觀察其治療潛能,以求進(jìn)一步的腦保護(hù)作用。方法1.骨髓巨噬細(xì)胞的培養(yǎng),取SHR-SP大鼠的股骨脛骨,沖洗骨髓腔,將得到的細(xì)胞懸液進(jìn)行培養(yǎng),并應(yīng)用巨噬細(xì)胞特異性蛋白抗體染色,在熒光顯微鏡下確定99%以上的細(xì)胞都是BMDM細(xì)胞。2.應(yīng)用A151、C151、LPS預(yù)處理骨髓巨噬細(xì)胞后,行OGD實(shí)驗(yàn),18小時(shí)后收取上清及細(xì)胞留用。一部分上清用于做酶聯(lián)免疫吸附測(cè)定((enzyme-linkedimmunosorbent assay, Elisa),一部分上清濃縮后測(cè)量蛋白濃度,和收集的裂解的細(xì)胞蛋白一起進(jìn)行免疫印記實(shí)驗(yàn)(Western blot)。3.應(yīng)用A151、C151、生理鹽水分別預(yù)處理SHR-SP大鼠,對(duì)大鼠行永久性大腦中動(dòng)脈離斷手術(shù),術(shù)后48小時(shí)進(jìn)行神經(jīng)功能評(píng)分,處死大鼠,收集腦、脾、腎血液等組織留用。4.收集的一部分大腦切片染色,應(yīng)用Image J (NIH, Bethesda, MD)軟件測(cè)量大鼠的腦梗死體積。5.一部分腦組織提取RNA,做Real-time PCR,檢測(cè)腦中NLRP3、Aim2、NLRP4的mRNA的表達(dá)。6.收集的血液進(jìn)行抗凝處理,一部分進(jìn)行血液化學(xué)物質(zhì)檢測(cè)以及血細(xì)胞計(jì)數(shù),另一部分離心后收集血漿進(jìn)行酶聯(lián)免疫檢測(cè)。7.收集的一部分腦及脾組織裂解后測(cè)量蛋白濃度,做Western blot以及Elisa。8.應(yīng)用JC-1試劑盒觀察線粒體膜電位。結(jié)果1.A151能夠明顯減少細(xì)胞培養(yǎng)液上清中的IL-1β、IL-1 a、IL-6, CINC1和TNFY的水平,和對(duì)照組的ODN C151相比,C151只能減少IL-6、CINC1的水平,對(duì)其他因子沒有影響。A151能夠明顯提高缺血缺氧狀態(tài)下BMDM的存活率。這一結(jié)果也證實(shí)了其他研究者提出的A151在炎癥細(xì)胞因子的中的作用并沒有細(xì)胞毒性作用的說法。2.通過蛋白免疫印跡法來進(jìn)一步檢測(cè)A151在IL-1βB的成熟和表達(dá)中的作用。結(jié)果發(fā)現(xiàn)A151可以減少用OGD處理后的BMDM的培養(yǎng)液上清中的成熟的IL-1β的表達(dá)。而且A151減少了成熟的·aspasel和NLRP3以及iNOS的表達(dá),但是A151對(duì)ASC, AIM2, NLRP1和NLRC4沒有影響。3.線粒體功能障礙與NLRP3炎性小體的激活有關(guān),本實(shí)驗(yàn)通過JC一1試劑盒檢測(cè)發(fā)現(xiàn)A151能減輕線粒體膜的去極化從而減少細(xì)胞的死亡。4.在實(shí)驗(yàn)中應(yīng)用永久性大腦中動(dòng)脈離斷手術(shù)模型研究A151的治療潛能作用發(fā)現(xiàn),與C151組和生理鹽水組相比較,術(shù)前三天,術(shù)前一天以及術(shù)后三小時(shí)腹腔注射A151組的腦梗死體積均顯著縮小,具有統(tǒng)計(jì)學(xué)意義。5.提取術(shù)后48小時(shí)后SHR-SP大鼠的腦組織的RNA,做Real-time PCR發(fā)現(xiàn)A151處理后的NLRP3的mRNA的表達(dá)明顯減少,而Aim2和NLRP4的mRNA的表達(dá)無明顯變化。結(jié)論1.A151減少LPS和OGD處理后的BMDM的死亡及炎性因子的釋放。2.A151可以減少OGD和LPS的處理下的BMDM內(nèi)的成熟的IL-1β和caspasel,并且能夠減少NLRP3 and iNOS的表達(dá)。3.A151能減輕BMDM細(xì)胞的線粒體膜的去極化。4.A151可以減輕永久性大腦中動(dòng)脈離斷手術(shù)的SHR-SP大鼠的腦的缺血性損害。5.A151能減少永久性大腦中動(dòng)脈離斷手術(shù)的SHR-SP大鼠的腦內(nèi)的NLRP3的mRNA的表達(dá)。
[Abstract]:Stroke is one of the most serious diseases for human being. Stroke is a high incidence, high rate of disability, high recurrence rate, high death rate, and high economic burden of "five high" disease. In China, stroke is the first cause of death. Immune inflammation plays an important role in the pathological process of the development of stroke. Inflammation is an organism's defense response to stimulation, which plays an important role in the organism. When stimulated by an irritation factor, it induces an inflammatory response to repair tissue and resist injury. Inflammation also causes adverse effects on the body and leads to immune system disorders. A variety of risk factors, including hypertension, atherosclerosis, diabetes, atrial fibrillation, vascular damage caused by smoking, and so on. More interestingly, cerebrovascular events lead to the release of damage associated molecular patterns (DAMPs), which enhances the innate immune response and eventually leads to brain damage. The effective treatment of acute ischemic stroke is to restore cerebral perfusion as early as possible in an effective time window, such as the clinical application of recombinant tissue type plasminogen activator (recombinant tissue plasminogen activator, rTPA) for ultra early venous thrombolysis, but the clinical effect is good, but the clinical effect is good, but the clinical effect is good, but the clinical effect is good, However, it is restricted by many factors such as the time window of treatment, the general situation of the patients and the complications such as bleeding after thrombolytic, so only about less than 20% of the patients can benefit. It is difficult to recover cerebral perfusion as early as possible in the clinical practice. The researchers focused on the study of the mechanism of cell protection, which kept the dynamic balance of the homeostasis in the cells after the ischemic and anoxic stress, thus protecting the brain cells from being destroyed. The experiment was successful in the animal body, but failed in the clinical transformation study. Nevertheless, in the International Stroke Organization Efforts have made great progress in the study of the pathological process of stroke. The inflammatory small body (Inflammasomes) is a polyprotein complex. As a part of the innate immunity, the cystine aspartate protein hydrolase -1 (caspase-1) can be activated by stress and infection to stimulate the external signal, thus producing interleukin 1 beta (IL-1 beta) and interleukin 18 (IL-18).Caspase-1 and IL-1 beta enhance inflammatory response and cell death. IL-1 beta plays an important role in many diseases, including cerebral ischemic damage. The mechanism has not been revealed. In the stroke experiment, the expression of IL-1 beta is increased with the occurrence of cerebral ischemia, and many experiments have confirmed that the production of IL-1 beta has the brain. It is worth noting that the levels of IL-1 beta in the blood and cerebrospinal fluid of human ischemic stroke are elevated. In the rat model, the levels of inflammatory small body related proteins after ischemic brain damage increase and the levels of inflammatory small body related proteins reduce the degree of damage. The damaged cells, including the nerve cells, can be released. Adenosine triphosphate (ATP), uridine three phosphoric acid (UTP), activates the ion channel P2X7 receptor on the microglia or macrophages, leading to the production of.Caspasel in the precursor of the inflammatory factor on the large molecular egg -NLRP3. Under the action of Caspasel, the mature IL-1 beta, IL-18 is converted from its precursors. Ischemia damage and cell death are caused by the action of Caspasel. The formation of DAMPs.DAMPs includes high mobility group protein 1 (HMGB1), heat shock protein HSP60, A beta, which can act on the Tool like receptor (TLR) on the surface of the cell, thereby increasing the gene expression of the inflammatory precursors. The production of cytokines and the formation of complement cause the increase of leukocyte infiltration and the damage of the brain, which can produce more DAM. Ps, further aggravating the damage. At the same time, the antigen released by the damaged cells also activates the adaptive immunity mediated by T cells. These recent developments have led to the need to reassess the role of inflammation and immunity in the pathophysiological process of stroke. The Nobel prize winner of the Nobel prize found the telomere hat at the end of the chromosome to protect the chromosome. To prevent its fusion, degradation and recombination, it lays the foundation for the study of aging and cancer. The mammalian telomere is composed of TTAGGG base pairs, which are released from the dead host cells and can reduce the inflammatory response to tissue damage. The synthesized oligonucleotide A151 is combined with four TTAGGG bases in thiosphosphates. On the skeleton,.A151 replicates the ability of telomere DNA to regulate the inflammatory response, including the regulation of IL-6 (IL-6), interleukin 12 (IL-12), interferon gamma (IFN gamma), macrophage inflammatory protein 2 (MIP-2) and tumor necrosis factor alpha (TNF alpha) as an anti inflammatory reaction agent, and its therapeutic potential has been in arthritis, endotoxic shock, and knife A induced viral hepatitis, ocular inflammation, lupus nephritis, atherosclerosis, and silica induced pulmonary inflammation are confirmed. It is essential that the pharmacodynamics and safety of thiophosphoric acid oligodeoxynucleotides have been confirmed in multiple clinical trials to confirm the inflammatory response of.A151 to cerebral ischemia On the basis of the role of IL-1 beta in ischemic brain damage and the success of A151 to improve the inflammatory factors of various diseases, if A151 can reduce the inflammatory response after cerebral ischemia and protect the cerebral ischemic damage, it will be ischemic stroke. Treatment provides a new bright spot. Bone marrow macrophages and microglia are the main sources of IL-1 beta during cerebral ischemia. After cerebral ischemia, monocytes are rapidly infiltrated into the brain and macrophages except the macrophages around the blood vessels. Therefore, bone marrow macrophages are used in the double treatment of LPS and OGD. To simulate the state of cerebral ischemia and hypoxia. The survival period of the stroke prone spontaneously hypertensive rats (SHR-SP rats) is short and prone to stroke. It is the most ideal animal model for the study of stroke. This experiment used the permanent middle cerebral artery disconnection model in SHR-SP rats. The A151 and the control agent oligonucleotide C151 (5'-TTCA AATTCAAATTCAAATTCAAA-3') is provided by the American food and Drug Administration (FDA) biological products evaluation and Research Center (CBER). Objective 1. in vitro part: Double synergistic treatment of bone marrow macrophages with LPS and OGD in order to simulate the ischemic and anoxic environment in the brain and to detect the immune inflammation of bone marrow macrophages of A151 after hypoxia and glucose deficiency. The role of the reaction to reduce the release of inflammatory factors, alleviate the inflammatory response and reduce the cell damage in.2. body parts: the permanent middle cerebral artery dissection operation model of SHR-SP rats will be used to observe the inflammatory causes of the SHR-SP rats after apoplexy, respectively, from the animal behavior, tissue, immunity, and gene levels. The effect of the child and the protective effect on the brain tissue, observe its therapeutic potential in order to further protect the brain. Method 1. bone marrow macrophages of 1. bone marrow were cultured, the femur tibia of the rats was taken and the bone marrow cavity was flushed. The cell suspension was cultured, and the macrophage specific protein antibody staining was used to determine 9 under the fluorescence microscope. More than 9% of the cells were BMDM cells.2. using A151, C151, LPS pretreatment of bone marrow macrophages, OGD experiment, 18 hours after the collection of supernatant and cell retention. Part of the supernatant for enzyme linked immunosorbent assay (enzyme-linkedimmunosorbent assay, Elisa), a division of the concentration of protein concentration after concentration, and the collection of lysed cells The immune imprinting experiment (Western blot).3. used A151, C151, and physiological saline to pretreat SHR-SP rats respectively. The rats were treated with permanent middle cerebral artery disconnection, and the nerve function score was performed 48 hours after the operation. The rats were killed and some tissues of brain, spleen, kidney and blood were collected for.4. collection and a part of the brain was stained and Image was applied. J (NIH, Bethesda, MD) software to measure the volume of cerebral infarction in rats.5. a part of the brain tissue extracted RNA, Real-time PCR, the expression of NLRP3, Aim2, NLRP4 mRNA in the brain for anticoagulant treatment, a part of blood chemical substances and blood cell count, and the other part of centrifugation to collect plasma for enzyme linked immunization The concentrations of protein in the brain and spleen tissues collected by.7. were measured, and the mitochondrial membrane potential was observed by Western blot and Elisa.8. using JC-1 kit. Results 1.A151 could significantly reduce the level of IL-1 beta, IL-1 a, IL-6, CINC1 and TNFY in the supernatant of cell culture. Level, no effect on other factors,.A151 can significantly increase the survival rate of BMDM under ischemic and anoxic state. This result also confirms the role of other researchers in the role of A151 in inflammatory cytokines and does not have cytotoxic effects..2. further detects the maturity and table of A151 in IL-1 beta B through protein immunoblotting. The results showed that A151 could reduce the expression of mature IL-1 beta in the supernatant of BMDM culture after OGD treatment. Moreover, A151 reduced the expression of mature, aspasel, NLRP3 and iNOS, but A151 has no effect on the activation of ASC, AIM2, NLRP1, and iNOS. This experiment is related to the activation of the inflammatory small body. JC 1 Kit detection showed that A151 could reduce the depolarization of mitochondrial membrane and reduce cell death..4. was used to study the therapeutic potential of A151 with permanent middle cerebral artery disconnection model, and compared with C151 group and saline group, three days before operation, one day before operation and three hours after operation to intraperitoneal injection of A151. The volume of cerebral infarction in the group was significantly reduced, with statistical significance of RNA in the brain tissue of SHR-SP rats 48 hours after.5. extraction. Real-time PCR found that the expression of mRNA in NLRP3 after A151 treatment was significantly reduced, but the expression of Aim2 and NLRP4 mRNA was not significantly changed. The release of.2.A151 can reduce the mature IL-1 beta and caspasel within the BMDM of the BMDM and reduce the NLRP3 and iNOS expression.3.A151 can reduce the mitochondrial membrane depolarization.4.A151 of the BMDM cells to reduce the ischemic damage to the brain of the permanent middle cerebral artery dissection operation. The expression of NLRP3 mRNA in the brain of SHR-SP rats after surgery for persistent middle cerebral artery occlusion.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R743.3

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