【摘要】：AS性缺血性心、腦血管疾病憑借其高發(fā)病率、高致殘率、高致死率,嚴(yán)重危害人類的生命健康。目前,促進(jìn)AS斑塊的穩(wěn)定性是防治心腦血管疾病的主要方法之一。炎癥反應(yīng)貫穿AS的整個(gè)病理過程,炎癥所介導(dǎo)的脂質(zhì)、能量代謝異常、氧化應(yīng)激、內(nèi)皮損傷、細(xì)胞凋亡等直接增加了AS斑塊的不穩(wěn)定性,提高了急性血管事件的發(fā)生率。近年來,越來越多的研究發(fā)現(xiàn),基于抗擊炎癥的治療方法能夠有效延緩AS的進(jìn)展、減少AS性疾病的發(fā)生。巨噬細(xì)胞通過分泌大量炎性介質(zhì),如細(xì)胞因子、趨化因子、黏附分子、基質(zhì)金屬酶等在AS炎癥反應(yīng)中發(fā)揮重要作用。在不同的刺激條件下,巨噬細(xì)胞可極化為促炎亞型(M1)或抗炎亞型(M2)。近年來,通過干預(yù)巨噬細(xì)胞極化的各個(gè)環(huán)節(jié),抑制巨噬細(xì)胞向M1亞型極化,促進(jìn)巨噬細(xì)胞向M2亞型極化逐漸成為AS及AS相關(guān)疾病防治的新策略。研究證實(shí),ox LDL是促使AS炎癥反應(yīng)啟動(dòng)和放大的重要致?lián)p因素,ox LDL能夠通過誘導(dǎo)巨噬細(xì)胞活化為促炎的M1型,介導(dǎo)一系列炎癥反應(yīng)的發(fā)生。盡管目前已經(jīng)發(fā)現(xiàn)一些信號(hào)通路參與調(diào)節(jié)ox LDL誘導(dǎo)的巨噬細(xì)胞極化,但具體機(jī)制尚未完全明確。因此,為了深入了解ox LDL影響巨噬細(xì)胞極化的可能機(jī)制,為AS性疾病的防治提供新的思路,我們進(jìn)行了以下三部分研究:第一部分ox LDL對(duì)巨噬細(xì)胞極化影響的研究目的:探究ox LDL對(duì)不同種屬來源巨噬細(xì)胞表型標(biāo)志物及相關(guān)細(xì)胞因子表達(dá)的影響,明確ox LDL誘導(dǎo)巨噬細(xì)胞極化的方向。方法:(1)給予小鼠RAW264.7巨噬細(xì)胞不同濃度ox LDL處理,檢測(cè)M1、M2亞型相關(guān)表型標(biāo)志物、細(xì)胞因子的表達(dá)與分泌水平。(2)給予人THP1巨噬細(xì)胞不同濃度ox LDL處理,檢測(cè)M1、M2亞型相關(guān)表型標(biāo)志物、細(xì)胞因子的表達(dá)水平。(3)誘導(dǎo)冠心病、急性大動(dòng)脈粥樣硬化性腦梗死患者及健康供者外周血中的單個(gè)核細(xì)胞為原代巨噬細(xì)胞,給予ox LDL處理,檢測(cè)M1、M2亞型相關(guān)表型標(biāo)志物及細(xì)胞因子的表達(dá)水平,并觀察細(xì)胞的形態(tài)變化。結(jié)果:(1)ox LDL處理后,小鼠RAW264.7巨噬細(xì)胞中M1表型標(biāo)志物i NOS及M1相關(guān)細(xì)胞因子TNF-α、IL-1β、MCP1的m RNA水平與蛋白水平明顯高于對(duì)照組,具有顯著性差異,p0.05;小鼠M2表型標(biāo)志物Arg1的m RNA水平與對(duì)照組無顯著性差異,p0.05,但其蛋白水平明顯低于對(duì)照組;M2相關(guān)細(xì)胞因子VEGF的表達(dá)僅在高濃度ox LDL處理時(shí)高于對(duì)照組,具有顯著性差異,p0.05。(2)ox LDL處理后,人THP1巨噬細(xì)胞中i NOS及TNF-α表達(dá)明顯高于對(duì)照組,具有顯著性差異,p0.05;人M2表型標(biāo)志物CD206及相關(guān)VEGF的表達(dá)無顯著性差異,p0.05。(3)ox LDL處理后,人原代巨噬細(xì)胞中M1相關(guān)基因的表達(dá)高于對(duì)照組;CD206的表達(dá)低于對(duì)照組,但VEGF的表達(dá)高于對(duì)照組;ox LDL處理后,原代巨噬細(xì)胞形態(tài)發(fā)生明顯改變。結(jié)論:ox LDL誘導(dǎo)不同種屬來源的巨噬細(xì)胞向M1亞型而不是M2亞型極化。第二部分ox LDL通過NF-κB-HIF-1β信號(hào)通路誘導(dǎo)巨噬細(xì)胞極化的研究目的:通過抑制巨噬細(xì)胞中NF-κB及HIF-1β表達(dá),探究二者在轉(zhuǎn)錄水平上對(duì)ox LDL誘導(dǎo)巨噬極化的調(diào)控作用及機(jī)制。方法:(1)采用不同時(shí)間/濃度梯度ox LDL處理小鼠RAW264.7巨噬細(xì)胞,檢測(cè)NF-κB信號(hào)通路的活化水平。(2)采用PTL預(yù)處理抑制NF-κB活性后,檢測(cè)ox LDL對(duì)小鼠巨噬細(xì)胞表型標(biāo)志物及細(xì)胞因子表達(dá)水平的影響。(3)誘導(dǎo)冠心病、急性大動(dòng)脈粥樣硬化性腦梗死患者及健康供者外周血中的單個(gè)核細(xì)胞為原代巨噬細(xì)胞,PTL預(yù)處理后,檢測(cè)ox LDL對(duì)巨噬細(xì)胞中M1、M2相關(guān)基因表達(dá)水平的影響,并觀察細(xì)胞形態(tài)變化。(4)不同時(shí)間/濃度梯度ox LDL處理小鼠巨噬細(xì)胞,檢測(cè)HIF家族蛋白表達(dá)水平。(5)采用sh RNA沉默小鼠巨噬細(xì)胞中HIF-1β,檢測(cè)ox LDL對(duì)巨噬細(xì)胞表型標(biāo)志物及細(xì)胞因子表達(dá)水平的影響。(6)分別抑制巨噬細(xì)胞中NF-κB與HIF-1β的表達(dá),探究ox LDL條件下NF-κB與HIF-1β之間的相互調(diào)節(jié)作用。結(jié)果:(1)ox LDL處理后,小鼠巨噬細(xì)胞中NF-κB信號(hào)通路中的經(jīng)典途徑及非經(jīng)典途徑均被激活。(2)PTL預(yù)處理能夠削弱ox LDL誘導(dǎo)的小鼠巨噬細(xì)胞中M1相關(guān)基因的表達(dá),促進(jìn)M2相關(guān)基因表達(dá),具有顯著性差異,p0.05。(3)PTL預(yù)處理能夠削弱ox LDL誘導(dǎo)的人原代巨噬細(xì)胞中M1相關(guān)基因及VEGF的表達(dá),促進(jìn)M2相關(guān)CD206表達(dá)增加,并阻斷ox LDL誘導(dǎo)的細(xì)胞形態(tài)改變。(4)ox LDL處理提高小鼠巨噬細(xì)胞中HIF的蛋白表達(dá)水平。(5)sh RNA沉默巨噬細(xì)胞中的HIF-1β能夠削弱ox LDL誘導(dǎo)的M1相關(guān)基因的表達(dá),促進(jìn)M2相關(guān)基因表達(dá)升高,具有顯著性差異,p0.05。(6)抑制NF-κB活化后,HIF-1β表達(dá)受抑制;沉默HIF-1β后,NF-κB活化不受影響。結(jié)論:(1)NF-κB與HIF-1β參與調(diào)控ox LDL誘導(dǎo)巨噬細(xì)胞向M1型極化。(2)抑制NF-κB、HIF-1β能夠調(diào)控ox LDL誘導(dǎo)的巨噬細(xì)胞向M2亞型方向極化。(3)NF-κB位于HIF-1β上游,調(diào)控HIF-1β的表達(dá)。第三部分ox LDL通過KDM4A/JMJD2A誘導(dǎo)巨噬細(xì)胞極化的研究目的:通過沉默去甲基化酶KDM4A的表達(dá),探究KDM4A在表觀遺傳水平上參與調(diào)控ox LDL誘導(dǎo)巨噬極化的機(jī)制。方法:(1)采用不同時(shí)間/濃度梯度ox LDL處理小鼠RAW264.7及THP1巨噬細(xì)胞,檢測(cè)KDM4A的表達(dá)水平。(2)采用sh RNA沉默小鼠巨噬細(xì)胞中的KDM4A,檢測(cè)ox LDL對(duì)巨噬細(xì)胞表型標(biāo)志物及細(xì)胞因子表達(dá)水平的影響。(3)分別抑制小鼠巨噬細(xì)胞中NF-κB、HIF-1β和KDM4A的表達(dá),探究ox LDL條件下KDM4A表達(dá)與NF-κB-HIF-1β信號(hào)通路之間的相互作用。(4)采用KDM4A抑制劑JIB-04,處理小鼠巨噬細(xì)胞,檢測(cè)細(xì)胞凋亡情況,探究KDM4A在維持巨噬細(xì)胞生存中的作用。結(jié)果:(1)ox LDL處理明顯增加小鼠RAW264.7及人THP1巨噬細(xì)胞KDM4A的表達(dá)水平。(2)sh RNA沉默巨噬細(xì)胞中的KDM4A能夠削弱ox LDL誘導(dǎo)的M1相關(guān)基因的表達(dá),促進(jìn)M2相關(guān)基因表達(dá)升高,具有顯著性差異,p0.05。(3)KDM4A的表達(dá)不依賴于NF-κB-HIF-1β信號(hào)通路,反之亦然。(4)JIB-04處理能夠增加巨噬細(xì)胞凋亡率,ox LDL部分削弱JIB-04介導(dǎo)的凋亡,具有顯著性差異,p0.05。結(jié)論:(1)KDM4A參與調(diào)控ox LDL誘導(dǎo)巨噬細(xì)胞向M1型極化。(2)KDM4A的表達(dá)與NF-κB-HIF-1β信號(hào)通路相互獨(dú)立。(3)KDM4A參與調(diào)控巨噬細(xì)胞存活。
[Abstract]:AS sex ischemic heart, cerebrovascular disease, with its high incidence, high disability rate and high mortality, seriously endangers human life and health. At present, promoting the stability of AS plaque is one of the main methods to prevent and cure cardiovascular and cerebrovascular diseases. The inflammatory reaction runs through the whole pathological process of AS, the lipid metabolism, the oxidative stress, and the oxidative stress. Skin injury, apoptosis and so on directly increase the instability of AS plaque and increase the incidence of acute vascular events. In recent years, more and more studies have found that the treatment based on anti inflammation can effectively delay the progress of AS and reduce the occurrence of AS diseases. Macrophages are chemotactic by secreting a large number of inflammatory mediators, such as cytokines. Factors, adhesion molecules, matrix metalloenzyme and so on play an important role in the AS inflammatory response. In different stimuli, macrophages can polarize proinflammatory subtype (M1) or anti-inflammatory subtype (M2). In recent years, the polarization of macrophage to M1 subtype is inhibited by interfering with each link of macrophage polarization to promote the gradual polarization of macrophages to the M2 subtype. As a new strategy for the prevention and control of AS and AS related diseases, it has been confirmed that ox LDL is an important factor contributing to the initiation and amplification of AS inflammatory reactions. Ox LDL can induce a series of inflammatory reactions by inducing macrophage activation as a pro-inflammatory M1, although some signal pathways are currently found to be involved in the regulation of macrophage fines induced by ox LDL. Therefore, in order to understand the possible mechanism of ox LDL's influence on macrophage polarization, and to provide new ideas for the prevention and control of AS sex diseases, we have conducted the following three parts: the first part of the research on the effect of ox LDL on the polarization of macrophages: To explore the ox LDL for the giant macrophages of different species. The influence of the expression of cell phenotype markers and related cytokines, and to clarify the direction of ox LDL induced polarization of macrophages. Methods: (1) the RAW264.7 macrophages in mice were treated with different concentrations of ox LDL, and M1, M2 subtype related phenotypic markers were detected, the expression of cytokines and secretory water were flat. (2) the different concentration ox LDL treatment of THP1 macrophages was given. Detection of M1, M2 subtype related phenotypic markers, the expression level of cytokines. (3) induced coronary heart disease, acute large atherosclerotic cerebral infarction and healthy donor peripheral blood mononuclear cells were primary macrophages, ox LDL treatment was given to detect the expression level of phenotypic markers and cytokines of M1, M2 subtypes, and to observe the expression level. Results: (1) after ox LDL treatment, the M1 phenotype markers of RAW264.7 macrophages in mice were I NOS and M1 related cytokines TNF- a, IL-1 beta, MCP1 m RNA level and protein level were significantly higher than those of the control group, but there was no significant difference between the mice and the control group. Its protein level was significantly lower than that of the control group; the expression of M2 related cytokine VEGF was higher than that of the control group at high concentration of ox LDL. The expression of I NOS and TNF- alpha in human THP1 macrophages was significantly higher than that in the control group after p0.05. (2) ox LDL treatment. There was no significant difference. After p0.05. (3) ox LDL treatment, the expression of M1 related genes in human primary macrophages was higher than that of the control group; the expression of CD206 was lower than that of the control group, but the expression of VEGF was higher than that of the control group; the morphology of primary macrophages changed obviously after ox LDL treatment. Conclusion: ox LDL induces macrophages from different species to M1 subtype. Not M2 subtype polarization. Second part ox LDL induced polarization of macrophage through NF- kappa B-HIF-1 beta signaling pathway: by inhibiting the expression of NF- kappa B and HIF-1 beta in macrophages, the regulatory role and mechanism of the two at the transcriptional level on ox LDL induced megagocytosis are explored. Methods: (1) use different time / concentration gradient ox LDL to treat small LDL. Mouse RAW264.7 macrophages were used to detect the activation level of NF- kappa B signaling pathway. (2) the effects of ox LDL on the phenotype markers of macrophages and the expression of cytokines in mice were detected by PTL pretreatment to inhibit NF- kappa B activity. (3) induced coronary heart disease, acute large atherosclerotic cerebral infarction and healthy donors in peripheral blood mononuclear cells The cells were primary macrophages. After PTL pretreatment, the effect of ox LDL on the expression level of M1 and M2 related genes in macrophages was detected and the morphological changes were observed. (4) the expression level of HIF family protein was detected by different time / concentration gradient ox LDL to detect the expression level of HIF family protein. (5) sh RNA was used to silence the HIF-1 beta in murine macrophages. The effects of phagocytic phenotypic markers and expression level of cytokines. (6) inhibition of the expression of NF- kappa B and HIF-1 beta in macrophages, and to explore the interaction between NF- kappa B and HIF-1 beta in ox LDL. Results: (1) the classical pathway and non classical pathway of NF- kappa B signal pathway in mouse macrophages were activated (2) PTL pretreatment can weaken the expression of M1 related genes in mouse macrophages induced by ox LDL, promote the expression of M2 related genes, and have significant differences. P0.05. (3) PTL pretreatment can weaken the expression of M1 related genes and VEGF in ox LDL induced human primary macrophages, promote the increase of M2 related expressions and block the cells induced by ox. Morphological changes. (4) ox LDL treatment enhanced the protein expression level of HIF in mouse macrophages. (5) HIF-1 beta in SH RNA silenced macrophages could weaken the expression of M1 related genes induced by ox LDL, promote the increase of the expression of M2 related genes, and have significant difference. P0.05. (6) inhibited the activation of NF- kappa. - kappa B activation is not affected. Conclusion: (1) NF- kappa B and HIF-1 beta participate in the regulation of ox LDL induced macrophages to M1 polarization. (2) inhibition of NF- kappa B, HIF-1 beta can regulate the orientation of macrophages induced by ox LDL. (3) Objective: To explore the mechanism of KDM4A at the epigenetic level to regulate ox LDL induced macrophage polarization through the expression of silencing demethylation enzyme KDM4A. Methods: (1) to use different time / concentration gradient ox LDL to treat mice RAW264.7 and THP1 macrophages and detect the level of KDM4A. (2) K in SH RNA murine macrophages DM4A, detect the effect of ox LDL on the expression of macrophage phenotypic markers and cytokines. (3) inhibit the expression of NF- kappa B, HIF-1 beta and KDM4A in mouse macrophages, and explore the interaction between KDM4A expression and NF- kappa B-HIF-1 beta signaling pathway in ox LDL conditions. (4) use the inhibitor to treat murine macrophages and detect the details. To explore the role of KDM4A in maintaining the survival of macrophages. Results: (1) ox LDL treatment significantly increased the expression level of KDM4A in mouse RAW264.7 and human THP1 macrophages. (2) KDM4A in SH RNA silent macrophages can weaken the expression of M1 related genes induced by ox LDL, and promote the increased expression of related genes, which has a significant difference. The expression of p0.05. (3) KDM4A is not dependent on the NF- kappa B-HIF-1 beta signaling pathway, and vice versa. (4) JIB-04 treatment can increase the apoptosis rate of macrophages, and ox LDL partially weakens JIB-04 mediated apoptosis. There is a significant difference in p0.05. conclusion: (1) KDM4A participates in the regulation of ox LDL to induce macrophage to polarization polarization. (2) Signal pathway is independent of each other. (3) KDM4A participates in regulating macrophage survival.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R543.5

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9 宋盛;周非凡;邢達(dá);;PDT誘導(dǎo)的凋亡細(xì)胞對(duì)巨噬細(xì)胞NO合成的影響[A];第七屆全國光生物學(xué)學(xué)術(shù)會(huì)議論文摘要集[C];2010年

10 張磊;朱建華;黃元偉;姚航平;;血管緊張素Ⅱ?qū)奘杉?xì)胞(THP-1重細(xì)胞)凝集素樣氧化低密度脂蛋白受體表達(dá)的影響[A];浙江省免疫學(xué)會(huì)第五次學(xué)術(shù)研討會(huì)論文匯編[C];2004年

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