發(fā)布時(shí)間：2018-07-11 17:27

  本文選題：間充質(zhì)干細(xì)胞 + 橫紋肌溶解　； 參考：《中國(guó)人民解放軍醫(yī)學(xué)院》2014年博士論文

【摘要】：研究背景橫紋肌溶解(rhabdomyolysis，RM)指任何原因引起的廣泛的橫紋肌細(xì)胞壞死,肌細(xì)胞內(nèi)容物外漏至細(xì)胞外液及血液循環(huán)中，導(dǎo)致急性腎損傷(acute kidney injury, AKI)、電解質(zhì)紊亂等一系列并發(fā)癥,重癥患者預(yù)后極差。與肌紅蛋白尿相關(guān)的AKI是創(chuàng)傷和非創(chuàng)傷性橫紋肌溶解最嚴(yán)重的并發(fā)癥，現(xiàn)有治療無法根本改善其預(yù)后。如何提高RM后腎小管上皮細(xì)胞壞死的修復(fù)再生、降低AKI死亡率，一直是醫(yī)學(xué)界研究的重大課題。近年來骨髓間充質(zhì)干細(xì)胞（mesenchymal stem cells, MSCs）在急慢性腎臟病中的應(yīng)用日益受到關(guān)注，給AKI的治療指明新的方向。多項(xiàng)研究均證實(shí)，MSCs治療可明顯改善腎小管損傷并有利于腎功能的恢復(fù)。巨噬細(xì)胞是天然免疫系統(tǒng)中重要的調(diào)節(jié)細(xì)胞,可分為經(jīng)典活化的M1型巨噬細(xì)胞和替代性活化的M2型巨噬細(xì)胞兩種極性狀態(tài)。M2型巨噬細(xì)胞具有抑制炎癥反應(yīng)，促進(jìn)組織重塑和再生修復(fù)的功能。體外研究中MSCs可與巨噬細(xì)胞相互作用，促進(jìn)M2型巨噬細(xì)胞的產(chǎn)生。那么，誘導(dǎo)M2型巨噬細(xì)胞的生成是否是MSCs減輕AKI的機(jī)制？目前尚無相關(guān)報(bào)道。本研究旨在建立RM所致AKI的小鼠動(dòng)物模型，探討MSCs是否通過誘導(dǎo)M2型巨噬細(xì)胞的生成來減輕AKI，為闡明MSCs治療減輕AKI的機(jī)制提供理論依據(jù)。 方法第一部分C57BL/6小鼠經(jīng)雙下肢肌肉注射50%甘油8ml/kg建立RM所致AKI模型，觀察第6h、12h、24h、48h、72h、96h、120h和168h時(shí)間點(diǎn)血尿素氮(BUN)、肌酐(Cr)和磷酸肌酸激酶(CK)的變化趨勢(shì)，以及腎臟、肌肉和肺臟的病理改變。將C57BL/6小鼠隨機(jī)分為Sham+生理鹽水(NS)組、Sham+MSCs組、RM+NS組和RM+MSCs組。6小時(shí)后，MSCs組給予1×106個(gè)紅色熒光蛋白（RFP）標(biāo)記的C57BL/6小鼠骨髓來源的MSCs尾靜脈注射, NS組給予等體積的生理鹽水尾靜脈注射；（1）生化檢測(cè)血BUN、Cr和CK水平（n=10）；（2）酶聯(lián)免疫吸附測(cè)定法（ELISA）檢測(cè)血清細(xì)胞因子IL-6、TNF-α和IL-10水平（n=5）；（3）光鏡觀察肌肉和腎臟病理損傷程度，計(jì)算腎小管壞死評(píng)分（n=4）；（4）PCNA免疫組化評(píng)價(jià)腎小管上皮細(xì)胞損傷后增殖情況（n=5）；（5）雙光子顯微鏡檢測(cè)RFP標(biāo)記的MSCs在RM模型小鼠各器官的定植情況（n=3）。 第二部分C57BL/6小鼠經(jīng)50%甘油8ml/kg肌肉注射建立RM模型，隨機(jī)分為RM+NS組和RM+MSCs組，n=5。取第24h、48h和72h的腎臟組織，免疫熒光技術(shù)檢測(cè)巨噬細(xì)胞（F4/80）浸潤(rùn)數(shù)量的變化和M2型巨噬細(xì)胞（CD206）浸潤(rùn)數(shù)量的變化；Western Blot檢測(cè)橫紋肌溶解后不同時(shí)間點(diǎn)的腎臟組織M2型巨噬細(xì)胞標(biāo)志物CD206的表達(dá)水平。第24小時(shí)，Western Blot檢測(cè)sham+NS組、sham+MSCs組、RM+NS組和RM+MSCs組的M2型巨噬細(xì)胞標(biāo)志物CD206表達(dá)情況。在損傷后第24小時(shí)，以MSCs治療的橫紋肌溶解AKI小鼠為研究對(duì)象，使用氯屈膦酸二鈉脂質(zhì)體清除其體內(nèi)的巨噬細(xì)胞，空白脂質(zhì)體作為對(duì)照，觀察兩組小鼠在第48h和72h血BUN、Cr和腎臟病理的改變。 第三部分將小鼠巨噬細(xì)胞系RAW264.7細(xì)胞分為三組：常規(guī)培養(yǎng)的細(xì)胞為M0組，脂多糖（LPS）2.5ug/ml刺激2h的細(xì)胞為M1組，LPS刺激后并與MSCs共培養(yǎng)72小時(shí)的細(xì)胞為M2組。使用細(xì)胞免疫熒光檢測(cè)三組細(xì)胞的巨噬細(xì)胞表面標(biāo)志物F4/80和M2型巨噬細(xì)胞表面標(biāo)志物CD206的表達(dá)，流式細(xì)胞技術(shù)檢測(cè)各組的CD206和IL-10表達(dá)，ELISA檢測(cè)不同時(shí)間點(diǎn)培養(yǎng)液上清IL-6、TNF-α和IL-10的水平（n=5）。使用氯膦酸二鈉脂質(zhì)體清除小鼠體內(nèi)巨噬細(xì)胞，然后建立橫紋肌溶解AKI模型，并隨即尾靜脈注射1×107個(gè)M0組、M1組和M2組的RAW264.7細(xì)胞（n=5）。在AKI的第72h檢測(cè)血BUN、Cr和腎臟病理。 結(jié)果本研究第一部分，成功建立了C57BL/6小鼠RM所致AKI模型，損傷后血BUN、Cr和CK進(jìn)行性升高，并觀察到CK于第24小時(shí)達(dá)峰值，BUN和Cr于第72小時(shí)達(dá)峰值的趨勢(shì)。第6h經(jīng)尾靜脈注射1×106個(gè)MSCs或等體積的NS對(duì)照，發(fā)現(xiàn)MSCs治療使RM小鼠血BUN、Cr和CK水平明顯下降(P0.01)，，血促炎細(xì)胞因子IL-6和TNF-α的水平明顯下降(P0.01)，血抑炎細(xì)胞因子IL-10的水平明顯升高(P0.01)。腎組織PAS染色顯示RM+MSCs組的腎小管損傷減輕，腎小管壞死評(píng)分下降。PCNA免疫組化見RM+MSCs組的腎小管上皮細(xì)胞明顯增生。雙光子顯微鏡活體檢測(cè)MSCs主要定植在肺臟和肌肉，腎臟未發(fā)現(xiàn)RFP標(biāo)記的MSCs，并用組織免疫熒光證實(shí)。 本研究第二部分，組織免疫熒光發(fā)現(xiàn)RM發(fā)生后，腎臟的巨噬細(xì)胞浸潤(rùn)逐漸增加，RM+MSCs組腎組織CD206陽性的M2型巨噬細(xì)胞提前出現(xiàn)。WesternBlot證實(shí)RM+MSCs組腎臟M2型巨噬細(xì)胞標(biāo)志物CD206的表達(dá)水平顯著高于RM+NS組(P0.01)，且表達(dá)在損傷后呈上升趨勢(shì)。不同組腎臟CD206表達(dá)分析發(fā)現(xiàn)：損傷后第24小時(shí)，僅RM+MSCs組出現(xiàn)CD206的明顯表達(dá)(P0.01)。MSCs治療AKI小鼠的巨噬細(xì)胞清除實(shí)驗(yàn)證實(shí)，在第24小時(shí)清除M2型巨噬細(xì)胞使第48h和72h小鼠的血BUN和Cr再次升高，伴腎臟損傷病理加重。 本研究第三部分，細(xì)胞免疫熒光檢測(cè)M0組、M1組及M2組的RAW264.7細(xì)胞均表達(dá)F4/80，僅M2組高表達(dá)CD206。流式細(xì)胞技術(shù)檢測(cè)發(fā)現(xiàn)M2組的RAW264.7細(xì)胞高表達(dá)CD206和IL-10。ELISA測(cè)定RAW264.7培養(yǎng)液上清細(xì)胞因子濃度，LPS使IL-6和TNF-α的水平升高，MSCs使IL-6和TNF-α的水平降低、IL-10的水平升高(P0.01)。氯屈膦酸二鈉脂質(zhì)體清除小鼠體內(nèi)的巨噬細(xì)胞后建立橫紋肌溶解AKI模型，空白脂質(zhì)體作為對(duì)照組，給予不同組巨噬細(xì)胞過繼轉(zhuǎn)移，損傷后第72小時(shí)發(fā)現(xiàn)接受M2組RAW264.7細(xì)胞小鼠的血清BUN、Cr和病理損傷均較對(duì)照組、M0組和M1組明顯減低(P0.01)。 結(jié)論（1）MSCs治療可調(diào)節(jié)體內(nèi)炎癥反應(yīng)，減輕RM所致AKI；（2）MSCs不通過直接定植于腎臟發(fā)揮保護(hù)作用；（3）MSCs治療促進(jìn)腎臟M2型巨噬細(xì)胞浸潤(rùn)的數(shù)量增加，清除巨噬細(xì)胞使已減輕的腎損傷再次加重（4）MSCs可在體外誘導(dǎo)巨噬細(xì)胞向M2型的轉(zhuǎn)換。（5）過繼轉(zhuǎn)移M2型巨噬細(xì)胞可改善RM所致的AKI。
[Abstract]:Background rhabdomyolysis (rhabdomyolysis, RM) refers to a wide range of rhabdomyocyte necrosis caused by any cause, muscle cell contents leaking into extracellular fluid and blood circulation, causing acute renal injury (acute kidney injury, AKI), electrolyte disorder and a series of disorders. The prognosis of severe patients is very poor. The AKI related to myoglobin urine is very poor. It is the most serious complication of traumatic and non traumatic rhabdomyolysis. Existing treatment can not improve its prognosis. How to improve the repair and regeneration of tubular necrosis of renal tubular cells after RM and reduce the mortality of AKI has been a major issue in the medical field. In recent years, bone marrow mesenchymal stem cells (mesenchymal stem cells, MSCs) are in acute and chronic kidney. A number of studies have confirmed that MSCs therapy can obviously improve renal tubular injury and benefit the recovery of renal function. Macrophages are important regulatory cells in the natural immune system, which can be divided into classical activated M1 type macrophages and alternative activated M2 type megagagi. .M2 type macrophages of two polar states have the function of inhibiting inflammatory response and promoting tissue remodeling and regeneration. In vitro, MSCs can interact with macrophages to promote the production of M2 type macrophages. Then, is the mechanism of inducing M2 type macrophages to be a mechanism for MSCs to reduce AKI? There is no related report. This study aims at this study. In the establishment of a mouse model of AKI induced by RM, it is discussed whether or not MSCs reduces AKI by inducing the formation of M2 type macrophages, providing a theoretical basis for clarifying the mechanism of MSCs therapy to alleviate AKI.
Methods in part 1, C57BL/6 mice were injected with 50% glycerol 8ml/kg to establish a RM induced AKI model, and the changes in blood urea nitrogen, creatinine and creatine kinase were observed at 6h, 12h, 24h, 48h, 72h, 96h, 120h and 168h time, and the pathological changes of the kidney, muscle and lungs. After.6 hours in group NS, group Sham+MSCs, group RM+NS and RM+MSCs, group MSCs was given MSCs tail vein of bone marrow of C57BL/6 mice with 1 x 106 red fluorescent protein (RFP) labeled C57BL/6 mice, and NS group was given equal volume of saline tail vein, and (1) biochemical test of BUN, Cr and levels; (2) enzyme linked immunosorbent assay Test serum cytokine IL-6, TNF- alpha and IL-10 level (n=5); (3) observe pathological damage of muscle and kidney and calculate renal tubular necrosis score (n=4); (4) PCNA immunohistochemistry to evaluate the proliferation of renal tubular epithelial cells (n=5); (5) double light microscopy detection of MSCs in RFP markers in each organ of RM model mice Condition (n=3).
The second part of C57BL/6 mice were injected with 50% glycerol and 8ml/kg to establish RM model. They were randomly divided into group RM+NS and RM+MSCs group. N=5. took the renal tissue of 24h, 48h and 72h. The changes in the number of macrophage (F4/80) infiltration and the quantity of M2 macrophage (CD206) were detected by immunofluorescence. The expression level of M2 type macrophage marker CD206 of the kidney tissue at the same time. Twenty-fourth hours, Western Blot was used to detect the expression of CD206 expression of M2 type macrophage markers in group sham+NS, sham+MSCs, RM+NS and RM+MSCs. Twenty-fourth hours after the injury, AKI mice were dissolved in the rhabdomydric acid two with MSCs treatment, and chlordric acid two was used. Sodium liposomes scavenged macrophages in vivo and blank liposomes as controls. The changes of BUN, Cr and renal pathology in 48h and 72h blood of two groups of mice were observed.
In the third part, the mouse macrophage RAW264.7 cells were divided into three groups: the conventional cultured cells were group M0, the lipopolysaccharide (LPS) 2.5ug/ml stimulated 2H cells in the M1 group, and the LPS stimulated and the MSCs co cultured for 72 hours was the M2 group. The macrophage surface markers, F4/80 and M2 macrophages, were detected by cell immunofluorescence. The expression of surface marker CD206, CD206 and IL-10 expression in each group were detected by flow cytometry. ELISA was used to detect the level of IL-6, TNF- A and IL-10 (n=5) at different time points. Chlorphosphonic acid two sodium liposomes were used to remove macrophages in mice, and then a rhabdomyolysis AKI model was established, and then 1 x 107 M0 groups were injected into the tail vein, M1. M1 RAW264.7 cells (n=5) in group M2 and group AKI were detected in BUN, Cr and renal pathology at 72h of AKI.
Results in the first part of this study, the AKI model induced by RM in C57BL/6 mice was successfully established. The blood BUN, Cr and CK were increased after injury, and the peak value of CK at twenty-fourth hours was observed, and the peak value of BUN and Cr at seventy-second hours was reached. 1 * 106 MSCs or equal volume NS controls were injected through the tail vein. Significantly decreased (P0.01), blood proinflammatory cytokines IL-6 and TNF- alpha significantly decreased (P0.01), the level of blood suppressor cell factor IL-10 increased significantly (P0.01). Renal tissue PAS staining showed that renal tubule injury in group RM+MSCs was reduced, renal tubular necrosis score decreased in.PCNA immunization, and the renal tubular epithelial cells in the RM+MSCs group were obviously proliferated. In vivo, MSCs was mainly colonized in lungs and muscles, and no RFP labeled MSCs was found in the kidneys. The results were confirmed by tissue immunofluorescence.
In the second part of this study, tissue immunofluorescence found that the infiltration of macrophages in the kidneys increased gradually, and the CD206 positive M2 macrophages in the RM+MSCs group showed.WesternBlot in group RM+MSCs, which showed that the expression level of CD206 of the M2 type macrophage marker in the RM+MSCs group was significantly higher than that in the RM+NS group (P0.01), and the expression increased after the injury. Trend. CD206 expression analysis in different groups of kidneys found that twenty-fourth hours after injury, only RM+MSCs group showed CD206 obvious expression (P0.01).MSCs treatment of AKI mice macrophage clearance experiment confirmed that the clearance of M2 type macrophages in twenty-fourth hours made 48h and 72h mice blood BUN and Cr increased again, with the pathological aggravation of renal injury.
The third part of this study, cell immunofluorescence test M0 group, M1 group and M2 group RAW264.7 cells all express F4/80, only M2 group high expression CD206. flow cytometry detection found that RAW264.7 cells in M2 group high expression CD206 and IL-10.ELISA determine the concentration of cell factor in the RAW264.7 culture liquid supernatant. The level of F- alpha and the level of IL-10 increased (P0.01). After scavenging of chlordronic acid two liposomes, the rhabdomyolysis AKI model was established. The blank liposomes were used as the control group, and the macrophages were adoptive and transferred in different groups. The serum BUN, Cr and pathological lesion of the M2 group RAW264.7 cell mice were found after seventy-second hours of injury. The injury was significantly lower in the M0 group and the M1 group than in the control group (P0.01).
Conclusion (1) MSCs therapy can regulate the inflammatory response in the body and reduce the AKI caused by RM; (2) MSCs does not use the direct colonization of the kidney to protect the kidney; (3) MSCs therapy promotes the increase in the number of M2 macrophage infiltration in the kidney, and clears the macrophages to aggravate the reduced renal injury (4) MSCs can induce the conversion of macrophage to M2 type in vitro. 5) adoptive transfer of M2 macrophages can improve the AKI. induced by RM.
【學(xué)位授予單位】：中國(guó)人民解放軍醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R692

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