紅斑狼瘡動脈粥樣硬化小鼠模型建立、發(fā)病機制及羥氯喹干預研究
發(fā)布時間：2018-07-17 16:41
【摘要】：研究目的1. 建立穩(wěn)定的系統(tǒng)性紅斑狼瘡動脈粥樣硬化動物模型。2. 利用小鼠模型,觀察系統(tǒng)性紅斑狼瘡(Systemic Lupus Erythematosus,SLE)對動脈粥樣硬化嚴重程度的影響。3. 進一步觀察狼瘡動脈粥樣硬化病變特點,尤其是免疫系統(tǒng)在動脈局部以及全身的改變,以及血脂變化特點,初步探討狼瘡動脈粥樣硬化發(fā)病的潛在機制。4. 研究常用的抗SLE藥物——羥氯喹(hydroxychloroquine, HCQ)對動脈粥樣硬化的影響,并初步觀察其對血脂以及炎癥反應的影響,為臨床上治療動脈粥樣硬化提供新的選擇。研究方法1. 應用apoE-/-以及C57BL/6小鼠,8周齡時通過腹腔內一次性注射0.5ml pristane構建SLE模型。部分小鼠通過飲水給予HCQ。2. 通過檢測自身抗體水平檢驗狼瘡模型構造是否成功,通過觀察動脈粥樣硬化斑塊是否形成明確動脈粥樣硬化模型構建是否成功。3.6個月后檢測尿蛋白,處死小鼠。分離血清,檢測血脂、白蛋白、總IgG、干擾素a (interferon-α, IFN-α)。4. 分離小鼠主動脈、心臟,進行主動脈大體油紅0染色,主動脈流式細胞術檢測CD45+、CD19+、CD68+、CD11c+細胞,主動脈瓣根部組織連續(xù)冰凍切片,進行油紅0染色、IgG免疫熒光染色、CD19+、CD68+、CD11c+細胞免疫熒光染色。5. 制備脾細胞懸液,流式細胞術檢測CD3+、CD19+、CD11b+、CD11c+細胞比例。結果1. 模型構建成功：注射了pristane的小鼠dsDNA抗體陽性。服用HCQ導致注射了pristane的小鼠dsDNA抗體陽性率降低。2. 小鼠外觀變化：部分狼瘡小鼠出現(xiàn)脫毛、皮膚出血,非狼瘡小鼠無上述現(xiàn)象。3. apoE-/-小鼠體重更重。4. 生化指標：apoE-/-小鼠LDL-C、TC高于C57BL/6小鼠。高脂飼料喂養(yǎng)的小鼠LDL-C、TC高于普通飲食小鼠。狼瘡發(fā)病對LDL-C無影響,狼瘡小鼠TC低于非狼瘡小鼠。HCQ對LDL-C、TC水平無顯著性影響,輕度降低血脂。狼瘡小鼠Alb低于非狼瘡小鼠,羥氯喹對Alb水平無影響。5. 動脈粥樣硬化斑塊進展情況：狼瘡小鼠主動脈斑塊面積大于非狼瘡小鼠,高脂飼料喂養(yǎng)小鼠斑塊面積多于普通飲食小鼠。至處死時,只有apoE-/-小鼠主動脈出現(xiàn)了斑塊,所有C57BL/6小鼠都沒有觀察到主動脈斑塊。狼瘡小鼠主動脈瓣根部斑塊面積大于非狼瘡小鼠,高脂飼料喂養(yǎng)的小鼠主動脈瓣根部斑塊面積多于普通飲食小鼠。只有apoE-/-小鼠主動脈瓣根部有斑塊,所有C57BL/6小鼠都沒有觀察到主動脈瓣根部斑塊。狼瘡對主動脈瓣根部斑塊的促進作用在高脂飼料喂養(yǎng)的apoE-/-小鼠中更明顯。羥氯喹具有抑制主動脈斑塊以及主動脈瓣根部斑塊形成的作用。6. 斑塊成分特點：狼瘡發(fā)病導致主動脈細胞增加,apoE-/-小鼠主動脈細胞數(shù)目多于C57BL/6小鼠。使用羥氯喹減少主動脈細胞數(shù)目。狼瘡小鼠主動脈白細胞總數(shù)、樹突狀細胞、巨噬細胞數(shù)量增加,B細胞減少。羥氯喹降低狼瘡小鼠主動脈白細胞、樹突狀細胞、巨噬細胞數(shù)目,增加狼瘡小鼠B細胞數(shù)目,對非狼瘡小鼠主動脈細胞數(shù)目無影響。狼瘡小鼠CD68+巨噬細胞和CD11c+樹突狀細胞定位基本一致。大量IgG沉積在主動脈瓣根部,B細胞也聚集在IgG沉積部位。狼瘡小鼠斑塊中IgG沉積增多,且更加質密,高脂飼料喂養(yǎng)導致IgG沉積增多。羥氯喹顯著減少apoE-/-小鼠主動脈斑塊IgG沉積。狼瘡小鼠血清IgG高于非狼瘡小鼠,高脂飼料喂養(yǎng)的小鼠血清IgG低于普通飲食小鼠,apoE-/-小鼠IgG低于C57BL/6小鼠。HCQ對血清IgG水平無影響。主動脈斑塊IgG沉積與血清IgG含量呈低度負相關。7. 狼瘡發(fā)病、小鼠動脈硬化易感的基因型導致脾臟指數(shù)增加,高脂飼料、羥氯喹對脾臟指數(shù)無影響。狼瘡小鼠脾臟淋巴細胞減少,高脂飼料也導致脾臟淋巴細胞減少。羥氯喹對小鼠脾臟B細胞比例無影響。羥氯喹增加狼瘡小鼠脾臟T細胞比例,對非狼瘡小鼠脾臟T細胞比例無影響。狼瘡小鼠脾臟CD11c+細胞增多,高脂飼料導致脾臟CD11c+細胞減少。羥氯喹對小鼠脾臟CD11c+細胞比例無顯著影響。狼瘡小鼠脾臟CD11b+細胞無顯著變化,羥氯喹對脾臟CD11b+細胞比例無影響。8. 狼瘡小鼠尿蛋白高于非狼瘡小鼠。HCQ不影響apoE-/-小鼠尿蛋白水平,但是降低C57BL/6小鼠尿蛋白水平。9. 個別狼瘡小鼠血清IFN-α升高,無統(tǒng)計學顯著性。結論1. apoE-/-、C57BL/6小鼠通過腹腔注射pristane可以成功誘導狼瘡疾病模型,2. apoE-/-小鼠容易出現(xiàn)主動脈粥樣硬化斑塊,C57BL/6小鼠不出現(xiàn)明顯斑塊。3. 狼瘡小鼠動脈粥樣硬化加重。4. 狼瘡小鼠的心血管傳統(tǒng)危險因素(總膽固醇)降低,但是狼瘡小鼠主動脈內炎性反應異常活躍(樹突狀細胞、巨噬細胞增多,B細胞減少,IgG沉積增多)；同時出現(xiàn)全身免疫狀態(tài)異常(脾臟淋巴細胞減少,樹突狀細胞增多,血清白蛋白降低,IgG升高)。5. 羥氯喹可以降低dsDNA抗體,可以減輕動脈粥樣硬化。6. 羥氯喹對血脂無顯著性影響,可以部分逆轉狼瘡所致的動脈粥樣硬化的斑塊成分異常以及脾臟細胞比例異常。7. 高脂飼料也可以通過升高血脂以及加重免疫系統(tǒng)異常從而加重動脈粥樣硬化。8. 狼瘡小鼠血清IFN-α無顯著變化。
[Abstract]:Objective 1. to establish a stable atherosclerotic animal model of systemic lupus erythematosus.2. model, and to observe the effect of systemic lupus erythematosus (Systemic Lupus Erythematosus, SLE) on the severity of atherosclerosis..3. further observed the characteristics of atherosclerotic lesions in lupus, especially the immune system in the arterial part. As well as the changes in the body and the characteristics of blood lipid changes, the potential mechanism of atherosclerosis in lupus is preliminarily discussed. The effect of the common anti SLE drug hydroxychloroquine (hydroxychloroquine, HCQ) on atherosclerosis and its effect on blood lipid and inflammatory reaction are preliminarily observed in order to treat atherosclerosis in clinical. Provide a new choice. Study method 1. apoE-/- and C57BL/6 mice were used to construct a SLE model by intraperitoneal injection of 0.5ml pristane at 8 weeks of age. Some mice were given HCQ.2. by drinking water to test the success of the lupus model by testing the level of autoantibodies, by observing whether atherosclerotic plaques formed a definite movement. Whether the arteriosclerosis model was successfully constructed.3.6 months later, the urine protein was detected, the mice were executed, the mice were killed, the serum was separated, the blood lipid, albumin, total IgG, a (interferon- alpha, IFN- alpha).4. were isolated from the aorta, the heart, the aorta gross oil red 0, and the active pulse flow cytometry for the detection of CD45+, CD19+, CD68+, CD11c+ cells, and aortic valve The root tissue was frozen in continuous frozen section to perform oil red 0 staining, IgG immunofluorescence staining, CD19+, CD68+, CD11c+ cell immunofluorescence staining.5. to prepare splenocytes suspension. Flow cytometry was used to detect CD3+, CD19+, CD11b+, and CD11c+ cell ratio. Results the 1. model was constructed successfully: the mice injected with pristane were positive. The positive rate of dsDNA antibody in istane mice decreased the appearance of.2. mice: some lupus mice were depilatory, skin bleeding, non lupus mice had no above phenomena, and.3. apoE-/- mice weighed more.4. biochemical indexes: apoE-/- mice LDL-C, TC higher than C57BL/6 mice. The disease had no effect on LDL-C. The TC of lupus mice was lower than that of non lupus mice,.HCQ had no significant effect on LDL-C, TC level had no significant effect on the level of blood lipid. The Alb of lupus mice was lower than non lupus mice. The level of hydroxychloroquine on Alb level had no effect on the progression of atherosclerotic plaque in.5.: the area of atherosclerotic plaque in lupus mice was greater than that of non lupus mice and high fat feed feeding. The patch area of the mice was more than that of the normal diet mice. Only the aorta appeared in the apoE-/- mice at the time of death. All the C57BL/6 mice did not observe the aortic plaque. The area of the aortic valve root plaque in the lupus mice was greater than that of the non lupus mice, and the area of the root plaque of the main artery valve in the high fat diet mice was more than that of the normal diet mice. Only apoE-/- mice had plaque at the root of the aortic valve, and no plaque in the aortic valve root was observed in all C57BL/6 mice. The promoting effect of lupus on the aortic valve root plaque was more obvious in the apoE-/- mice fed by high fat diet. Hydroxychloroquine has the effect of inhibiting the atherosclerotic plaque of the aorta and the plaque formation of the main artery valve at the root of the aorta. Composition characteristics: the incidence of lupus caused the increase of aortic cells, and the number of aorta cells in apoE-/- mice was more than that of C57BL/6 mice. The number of aortic cells was reduced by hydroxychloroquine. The total number of leukocytes, dendritic cells, macrophages and B cells decreased in lupus mice. The hydroxychloroquine decreased the white blood cells and dendritic cells in lupus mice The number of macrophages and macrophages increased the number of B cells in lupus mice. There was no effect on the number of aortic cells in non lupus mice. The localization of CD68+ macrophages and CD11c+ dendritic cells in lupus mice was basically the same. A large number of IgG were deposited at the root of the aortic valve, and the B cells were also gathered at the IgG deposition position. The IgG deposition in lupus mice increased and increased. Dense, high fat feed led to the increase of IgG deposition. Hydroxychloroquine significantly reduced the IgG deposition in aortic plaque in apoE-/- mice. The serum IgG of lupus mice was higher than non lupus mice, the serum IgG of mice fed with high fat diet was lower than that of normal diet mice, and IgG in apoE-/- mice was less than.HCQ in C57BL/6 mice. The product and serum IgG content showed low negative correlation with.7. lupus, and the susceptible genotype of arteriosclerosis in mice resulted in the increase of spleen index. High fat diet, hydroxychloroquine had no effect on spleen index. The spleen lymphocyte of lupus mice decreased, and high fat diet also resulted in the decrease of spleen lymphocyte. Hydroxychloroquine had no effect on the proportion of spleen B cells in mice. The proportion of T cells in the spleen of lupus mice was increased by chloroquine. The proportion of spleen T cells in non lupus mice was not affected. The spleen CD11c+ cells in lupus mice increased and the high fat feed led to the decrease of spleen CD11c+ cells. The proportion of CD11c+ cells in spleen of mice was not significantly affected by hydroxychloroquine. The spleen CD11b+ cells in lupus mice were not significantly changed, and hydroxychloroquine was used to the spleen CD11b+. No effect of cell ratio on urinary protein of.8. lupus mice was higher than that of non lupus mice,.HCQ did not affect the level of urine protein in apoE-/- mice, but the level of IFN- alpha in serum of C57BL/6 mice was lower than that of apoE-/- mice, and there was no statistical significance. Conclusion 1. apoE-/-, C57BL/6 mice can successfully induce lupus disease through abdominal cavity injection of pristane. Models, 2. apoE-/- mice were prone to atherosclerotic atherosclerotic plaques, C57BL/6 mice did not have obvious plaque in.3. lupus mice and the cardiovascular traditional risk factors (total cholesterol) decreased, but the inflammatory reaction in the aorta of lupus mice was abnormally active (dendritic cells, macrophages increased, B thin). At the same time, the immune state of the spleen was decreased, the immune state of the spleen was decreased, the increase of dendritic cells, the decrease of serum albumin, the increase of serum albumin, and the increase of IgG..5. hydroxychloroquine could reduce the dsDNA antibody, which could reduce the unmarked effect of.6. hydroxychloroquine on the blood lipid, and could partly reverse the atherosclerotic artery atherosclerosis caused by lupus. Abnormal atherosclerotic plaque composition and abnormal proportion of spleen cells.7. high fat diet can also increase serum IFN- alpha in atherosclerotic.8. lupus mice by increasing blood lipid and aggravating immune system abnormalities.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R593.241;R543.5;R-332
本文編號：2130271
[Abstract]:Objective 1. to establish a stable atherosclerotic animal model of systemic lupus erythematosus.2. model, and to observe the effect of systemic lupus erythematosus (Systemic Lupus Erythematosus, SLE) on the severity of atherosclerosis..3. further observed the characteristics of atherosclerotic lesions in lupus, especially the immune system in the arterial part. As well as the changes in the body and the characteristics of blood lipid changes, the potential mechanism of atherosclerosis in lupus is preliminarily discussed. The effect of the common anti SLE drug hydroxychloroquine (hydroxychloroquine, HCQ) on atherosclerosis and its effect on blood lipid and inflammatory reaction are preliminarily observed in order to treat atherosclerosis in clinical. Provide a new choice. Study method 1. apoE-/- and C57BL/6 mice were used to construct a SLE model by intraperitoneal injection of 0.5ml pristane at 8 weeks of age. Some mice were given HCQ.2. by drinking water to test the success of the lupus model by testing the level of autoantibodies, by observing whether atherosclerotic plaques formed a definite movement. Whether the arteriosclerosis model was successfully constructed.3.6 months later, the urine protein was detected, the mice were executed, the mice were killed, the serum was separated, the blood lipid, albumin, total IgG, a (interferon- alpha, IFN- alpha).4. were isolated from the aorta, the heart, the aorta gross oil red 0, and the active pulse flow cytometry for the detection of CD45+, CD19+, CD68+, CD11c+ cells, and aortic valve The root tissue was frozen in continuous frozen section to perform oil red 0 staining, IgG immunofluorescence staining, CD19+, CD68+, CD11c+ cell immunofluorescence staining.5. to prepare splenocytes suspension. Flow cytometry was used to detect CD3+, CD19+, CD11b+, and CD11c+ cell ratio. Results the 1. model was constructed successfully: the mice injected with pristane were positive. The positive rate of dsDNA antibody in istane mice decreased the appearance of.2. mice: some lupus mice were depilatory, skin bleeding, non lupus mice had no above phenomena, and.3. apoE-/- mice weighed more.4. biochemical indexes: apoE-/- mice LDL-C, TC higher than C57BL/6 mice. The disease had no effect on LDL-C. The TC of lupus mice was lower than that of non lupus mice,.HCQ had no significant effect on LDL-C, TC level had no significant effect on the level of blood lipid. The Alb of lupus mice was lower than non lupus mice. The level of hydroxychloroquine on Alb level had no effect on the progression of atherosclerotic plaque in.5.: the area of atherosclerotic plaque in lupus mice was greater than that of non lupus mice and high fat feed feeding. The patch area of the mice was more than that of the normal diet mice. Only the aorta appeared in the apoE-/- mice at the time of death. All the C57BL/6 mice did not observe the aortic plaque. The area of the aortic valve root plaque in the lupus mice was greater than that of the non lupus mice, and the area of the root plaque of the main artery valve in the high fat diet mice was more than that of the normal diet mice. Only apoE-/- mice had plaque at the root of the aortic valve, and no plaque in the aortic valve root was observed in all C57BL/6 mice. The promoting effect of lupus on the aortic valve root plaque was more obvious in the apoE-/- mice fed by high fat diet. Hydroxychloroquine has the effect of inhibiting the atherosclerotic plaque of the aorta and the plaque formation of the main artery valve at the root of the aorta. Composition characteristics: the incidence of lupus caused the increase of aortic cells, and the number of aorta cells in apoE-/- mice was more than that of C57BL/6 mice. The number of aortic cells was reduced by hydroxychloroquine. The total number of leukocytes, dendritic cells, macrophages and B cells decreased in lupus mice. The hydroxychloroquine decreased the white blood cells and dendritic cells in lupus mice The number of macrophages and macrophages increased the number of B cells in lupus mice. There was no effect on the number of aortic cells in non lupus mice. The localization of CD68+ macrophages and CD11c+ dendritic cells in lupus mice was basically the same. A large number of IgG were deposited at the root of the aortic valve, and the B cells were also gathered at the IgG deposition position. The IgG deposition in lupus mice increased and increased. Dense, high fat feed led to the increase of IgG deposition. Hydroxychloroquine significantly reduced the IgG deposition in aortic plaque in apoE-/- mice. The serum IgG of lupus mice was higher than non lupus mice, the serum IgG of mice fed with high fat diet was lower than that of normal diet mice, and IgG in apoE-/- mice was less than.HCQ in C57BL/6 mice. The product and serum IgG content showed low negative correlation with.7. lupus, and the susceptible genotype of arteriosclerosis in mice resulted in the increase of spleen index. High fat diet, hydroxychloroquine had no effect on spleen index. The spleen lymphocyte of lupus mice decreased, and high fat diet also resulted in the decrease of spleen lymphocyte. Hydroxychloroquine had no effect on the proportion of spleen B cells in mice. The proportion of T cells in the spleen of lupus mice was increased by chloroquine. The proportion of spleen T cells in non lupus mice was not affected. The spleen CD11c+ cells in lupus mice increased and the high fat feed led to the decrease of spleen CD11c+ cells. The proportion of CD11c+ cells in spleen of mice was not significantly affected by hydroxychloroquine. The spleen CD11b+ cells in lupus mice were not significantly changed, and hydroxychloroquine was used to the spleen CD11b+. No effect of cell ratio on urinary protein of.8. lupus mice was higher than that of non lupus mice,.HCQ did not affect the level of urine protein in apoE-/- mice, but the level of IFN- alpha in serum of C57BL/6 mice was lower than that of apoE-/- mice, and there was no statistical significance. Conclusion 1. apoE-/-, C57BL/6 mice can successfully induce lupus disease through abdominal cavity injection of pristane. Models, 2. apoE-/- mice were prone to atherosclerotic atherosclerotic plaques, C57BL/6 mice did not have obvious plaque in.3. lupus mice and the cardiovascular traditional risk factors (total cholesterol) decreased, but the inflammatory reaction in the aorta of lupus mice was abnormally active (dendritic cells, macrophages increased, B thin). At the same time, the immune state of the spleen was decreased, the immune state of the spleen was decreased, the increase of dendritic cells, the decrease of serum albumin, the increase of serum albumin, and the increase of IgG..5. hydroxychloroquine could reduce the dsDNA antibody, which could reduce the unmarked effect of.6. hydroxychloroquine on the blood lipid, and could partly reverse the atherosclerotic artery atherosclerosis caused by lupus. Abnormal atherosclerotic plaque composition and abnormal proportion of spleen cells.7. high fat diet can also increase serum IFN- alpha in atherosclerotic.8. lupus mice by increasing blood lipid and aggravating immune system abnormalities.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R593.241;R543.5;R-332
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