本文選題：雷帕霉素 + 細胞自噬��； 參考：《浙江大學》2013年博士論文

【摘要】：支氣管哮喘(簡稱哮喘)是一種以嗜酸性粒細胞(Eosinophils, Eos)、肥大細胞和T淋巴細胞浸潤為主的氣道慢性炎癥性疾病,表現(xiàn)為氣道高反應(yīng)性和可逆性氣流受限。其中嗜酸性粒細胞是哮喘過敏性氣道炎癥反應(yīng)的主要效應(yīng)細胞,Eos與哮喘發(fā)病之間存在直接因果關(guān)系。研究發(fā)現(xiàn),嗜酸性粒細胞在哮喘發(fā)病過程中參與多種功能調(diào)控,包括抗原提呈,細胞因子、趨化因子、顆粒介質(zhì)以及白三烯的釋放等。嗜酸性粒細胞是由骨髓共同髓系祖細胞(CMP)經(jīng)由粒-單核系祖細胞(GMP),由嗜酸性粒細胞祖細胞(EoP)定向分化成熟。嗜酸性粒細胞分化涉及多種轉(zhuǎn)錄因子(GATA-1等)和細胞因子,如白介素3(IL-3),IL-5,粒-單核集落刺激因子(GM-CSF),其中IL-5對Eos最終分化成熟起最主要的調(diào)節(jié)作用。然而,目前對于哮喘發(fā)病過程中Eos調(diào)控機制的研究并不多. 細胞自噬(autophagy)是機體一種重要的防御和保護機制。在某些特定的微環(huán)境條件(如饑餓,生長素缺乏)下,細胞內(nèi)形成一種雙層膜結(jié)構(gòu)的囊泡,細胞自噬體(autophagosomes),并同時捕獲細胞內(nèi)的受損的細胞器(如線粒體,內(nèi)質(zhì)網(wǎng))和變性的蛋白質(zhì)等；然后該囊泡與溶酶體溶合,形成自噬溶酶體(autolysosomes)。在溶酶體水解酶等的作用下,自噬體所包含的各種細胞器和生物大分子得以消化和降解,從而為重新合成新的生物大分子提供原料和能量。因此從本義上講,細胞自噬是機體保持內(nèi)穩(wěn)態(tài)(homeostasis)和適應(yīng)微環(huán)境改變的一種重要的自我調(diào)節(jié)和保護機制。然而,在某些特定的條件下,細胞器和各種生物大分子的過量消耗最終會導致細胞的另一種程序性死亡,細胞自噬死亡(autophagic cell death)。由于細胞自噬能保護或者促進細胞死亡,因此在不同的疾病病變過程中,其功能截然不同。越來越多的研究表明,自噬在機體的免疫、感染、炎癥、腫瘤、心血管病、神經(jīng)退行性病的發(fā)病中具有十分重要的作用。然而,細胞自噬在呼吸系統(tǒng)的研究并不多。新近有研究開創(chuàng)性地闡明了細胞自噬在吸煙誘導的氣道上皮細胞損傷以及慢性阻塞性肺疾病(COPD)形成過程中的重要調(diào)控作用。然而,細胞自噬在支氣管哮喘分子發(fā)病機制中的作用鮮有研究報導。 雷帕霉素(rapamycin)是經(jīng)典的細胞自噬誘導劑,是1975年從加拿大Easter島上的吸水鏈霉菌中提取的一種大環(huán)內(nèi)酯類抗生素。雷帕霉素的主要作用靶點,哺乳動物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)能接受并整合生長因子、能量、氧氣和氨基酸四大主要信號,參與調(diào)節(jié)能量代謝、蛋白質(zhì)、脂質(zhì)、細胞器的合成以及細胞自噬等生理過程,在細胞的生長、增殖、分化和凋亡中起著重要的調(diào)控作用,從而維持機體與細胞的穩(wěn)態(tài)平衡。研究發(fā)現(xiàn)雷帕霉素在哮喘動物模型中的作用并不一致,有報道發(fā)現(xiàn)雷帕霉素能抑制過敏性氣道炎癥,氣道高反應(yīng)性,杯狀細胞化生和IgE產(chǎn)生,但也有部分研究認為雷帕霉素對過敏性氣道炎癥和氣道高反應(yīng)性沒有影響。然而,最關(guān)鍵的是這些研究均只簡單利用雷帕霉素體內(nèi)干預(yù)觀察哮喘表型,并未闡明雷帕霉素及mTOR在哮喘發(fā)病機制中起到關(guān)鍵調(diào)控作用及其具體機制。 越來越多的研究發(fā)現(xiàn)細胞自噬和mTOR在造血干細胞分化和增殖中起到重要作用。自噬缺陷可抑制紅系造血導致嚴重貧血、抑制T淋巴細胞、B淋巴細胞數(shù)目和功能,而mTOR通過調(diào)控T細胞分化、功能、代謝參與調(diào)控適應(yīng)性免疫應(yīng)答。由此,我們假設(shè)細胞自噬和mTOR也參與骨髓粒系祖細胞尤其是嗜酸性粒細胞分化的調(diào)控,并進一步探討其在以嗜酸性粒細胞氣道炎癥為主要表現(xiàn)的整體哮喘模型中的可能作用與貢獻,從而為哮喘分子發(fā)病機制的研究開拓新的視野,為哮喘臨床的防治提供新的靶點。 本實驗分兩部分進行研究：(1)探求雷帕霉素及mTOR在哮喘氣道炎癥和骨髓嗜酸性粒細胞分化中的作用；(2)利用細胞自噬相關(guān)基因敲除小鼠Beclin1+/-和骨髓移植技術(shù),分別闡明細胞自噬在氣道上皮細胞損傷和骨髓嗜酸性粒細胞分化中的不同調(diào)控作用。 第一部分雷帕霉素在哮喘氣道炎癥和嗜酸粒細胞分化中的作用研究 目的：研究雷帕霉素干預(yù)對哮喘氣道炎癥的影響,并探討雷帕霉素在OVA誘導肺組織T細胞免疫應(yīng)答及骨髓嗜酸性粒細胞分化過程中的調(diào)控作用。 方法：健康雌性C57BL/6小鼠,隨機分為四組：生理鹽水對照組(SHAM組)、模型組(OVA組)、雷帕霉素對照組(SHAM+RAPA組)、雷帕霉素哮喘組(OVA+RAPA組)。以卵白蛋白(OVA)致敏和激發(fā)建立哮喘模型,生理鹽水對照組以同等劑量的生理鹽水代替OVA,雷帕霉素組在每次抗原激發(fā)前1小時進行腹腔注射(1mg/kg)。于最后一次抗原激發(fā)后24小時檢測肺泡灌洗液(BALF)、外周血和骨髓中的嗜酸性粒細胞數(shù)；肺組織病理切片觀察氣道炎癥細胞浸潤情況,ELISA檢測血清中IL-5,IL-13水平。流式細胞術(shù)檢測和分析肺組織Th2, Th17, Treg各T細胞亞群的比例,同時檢測骨髓中嗜酸性粒細胞祖細胞(EoP, Lin-Sca-l-CD34+IL-5Ra+c-Kitl0)的比例。Western blot檢測骨髓嗜酸性粒細胞分化過程中mTOR水平變化,體外克隆形成試驗及骨髓Eos誘導分化培養(yǎng)檢測雷帕霉素干預(yù)對骨髓嗜酸性粒細胞分化及功能的影響。最后利用IL-5轉(zhuǎn)基因小鼠NJ.1638,連續(xù)3天腹腔注射雷帕霉素,檢測外周血和骨髓中嗜酸性粒細胞數(shù),ELISA檢測血清中IL-5水平,流式細胞術(shù)檢測骨髓EoP的比例以及嗜酸性粒細胞凋亡情況。 結(jié)果：雷帕霉素干預(yù)后顯著緩解OVA誘導的氣道過敏性炎癥,但是不影響肺組織中Th2細胞,Th17細胞和Treg水平。雷帕霉素抑制了氣道局部以及外周血,骨髓嗜酸性粒細胞數(shù)目,但是并不改變血清IL-5水平。體外克隆形成試驗和骨髓Eos誘導分化培養(yǎng)發(fā)現(xiàn),雷帕霉素可以直接抑制IL-5介導的嗜酸性粒細胞分化及培養(yǎng)上清Eos分泌IL-6和IL-13的水平。離體骨髓克隆形成試驗及骨髓流式細胞術(shù)檢測結(jié)果提示,雷帕霉素對嗜酸性粒細胞分化的抑制最終導致骨髓嗜酸性粒細胞祖細胞的聚集。對IL-5轉(zhuǎn)基因小鼠NJ.1638的研究同樣證實了雷帕霉素對外周血和骨髓嗜酸性粒細胞數(shù)的抑制作用及骨髓EoP的聚集,并不依賴其血清高表達IL-5水平的改變,也不影響嗜酸性粒細胞的凋亡。 結(jié)論：雷帕霉素可以緩解哮喘小鼠氣道過敏性炎癥,可能是通過抑制骨髓嗜酸性粒細胞分化及功能,而對Eos凋亡和肺組織T細胞免疫無明顯影響。 第二部分細胞自噬在哮喘氣道炎癥和嗜酸粒細胞分化中的作用研究 目的：研究細胞自噬敲除對哮喘整體模型的影響,并探討細胞自噬在OVA誘導的氣道上皮細胞損傷和骨髓嗜酸性粒細胞分化過程中的不同調(diào)控作用。 方法：通過Western blot檢測哮喘小鼠骨髓及體外嗜酸性粒細胞誘導分化過程中自噬水平變化,并利用細胞自噬相關(guān)基因缺陷小鼠Beclin1+/-,通過瑞士-吉姆薩染色分析其外周血和骨髓中嗜酸性粒細胞的水平,流式細胞術(shù)檢測其骨髓嗜酸性粒細胞祖細胞水平,并通過甲基纖維素克隆形成試驗檢測其骨髓嗜酸性粒細胞分化能力。同時利用Beclin1+/-小鼠及其同窩生WT小鼠以O(shè)VA致敏和激發(fā)建立哮喘模型,隨機分組如下：野生型生理鹽水對照組(WT/NS),野生型哮喘模型組(WT/OVA),Beclin1+/-小鼠生理鹽水對照組(BECN/NS)和Beclin1+/-小鼠哮喘模型組(BECN/OVA)。末次激發(fā)后24小時,采用有創(chuàng)方法測定小鼠氣道反應(yīng)性,并檢測氣道灌洗液中的白細胞總數(shù)和嗜酸性粒細胞數(shù)；肺組織病理切片觀察氣道炎癥細胞浸潤和粘液分泌情況,電鏡觀察哮喘小鼠氣道上皮細胞自噬泡聚集情況。體外培養(yǎng)人正常肺上皮細胞(BEAS-2B),Western blot檢測OVA體外干預(yù)過程中自噬水平變化,Q-PCR檢測饑餓誘導自噬及IL-13體外干預(yù)對粘蛋白MUC5AC mRNA的表達情況。最后采用骨髓移植的方法,白硝胺+環(huán)磷酰胺聯(lián)合化療毀損野生型小鼠骨髓造血系統(tǒng),然后將Beclin1+/-小鼠或同窩生野生型小鼠骨髓移植至野生型小鼠并重建其造血系統(tǒng),OVA誘導建立哮喘模型,根據(jù)回輸骨髓不同分兩組：WT-WT-OVA組和BECN-WT-OVA組,觀察骨髓局部自噬敲除對哮喘整體模型氣道高反應(yīng)和氣道炎癥的貢獻。 結(jié)果：細胞自噬相關(guān)基因敲除小鼠Beclin1+/-,與同窩生野生型(WT)小鼠相比,外周血和骨髓中嗜酸性粒細胞數(shù)目顯著增多,骨髓EoP水平雖有下降趨勢,但無統(tǒng)計學意義。體外Eos誘導分化過程中LC3B蛋白水平的改變提示細胞自噬參與骨髓嗜酸性粒細胞分化。體外克隆形成試驗直接證實,Beclin1+/-小鼠骨髓生成嗜酸性粒細胞克隆形成單位能力增加。但Beclin1+/-小鼠抗原激發(fā)后氣道反應(yīng)性、氣道炎癥、粘液高分泌,與野生型小鼠模型組相比并未惡化,反而出現(xiàn)明顯減輕。同時發(fā)現(xiàn),雖然哮喘小鼠骨髓中LC3B蛋白水平下降,但電鏡可見哮喘氣道上皮細胞中存在細胞自噬泡聚集。并且體外實驗表明,OVA干預(yù)可上調(diào)LC3B蛋白水平,饑餓誘導自噬可進一步增強IL-13介導的BEAS-2B細胞MUC5AC mRNA的表達。在骨髓移植實驗中,Beclin1+/"小鼠骨髓回輸?shù)南∈?BECN-WT-OVA組),氣道反應(yīng)性和氣道炎癥都明顯高于野生型小鼠骨髓回輸?shù)南∈?WT-WT-OVA組)。 結(jié)論：細胞自噬敲除雖然在動物模型中整體表現(xiàn)為可以緩解哮嗤小鼠氣道過敏性炎癥,氣道高反應(yīng)性和粘液高分泌,但細胞自噬在氣道局部損傷和骨髓Eos分化過程中可能存在兩種完全相反的調(diào)控機制。自噬敲除抑制了OVA誘導的氣道上皮細胞損傷從而緩解了哮喘表型,而在骨髓嗜酸性粒細胞分化過程中則促進了其分化能力從而惡化了哮喘氣道炎癥。我們的研究提示對細胞自噬和mTOR信號通路的研究有望為哮喘的防治提供新的靶點。
[Abstract]:Bronchial asthma (asthma) is a chronic airway inflammatory disease characterized by eosinophil (Eosinophils, Eos), mast cell and T lymphocyte infiltration, characterized by airway hyperresponsiveness and reversible airflow limitation. Eosinophils are the main effector cells of asthma allergic airway inflammation, Eos and asthma There is a direct causal relationship between diseases. The study found that eosinophils participate in a variety of functional regulation during the pathogenesis of asthma, including antigen presentation, cytokine, chemokines, granular media and release of leukotrienes. Eosinophils are derived from bone marrow common myeloid progenitor cells (CMP) via granulocyte mononuclear progenitor cells (GMP), by eosinophilic acid. Granulocyte progenitor cells (EoP) are differentiated and mature. Eosinophil differentiation involves a variety of transcription factors (GATA-1) and cytokines, such as interleukin 3 (IL-3), IL-5, and granulocyte colony stimulating factor (GM-CSF), of which IL-5 plays the most important role in the final differentiation and maturation of Eos. However, at present, the regulation mechanism of Eos in the pathogenesis of asthma is present. There is not much research.
Cellular autophagy (autophagy) is an important mechanism for the defense and protection of the body. In certain specific microenvironmental conditions (such as starvation, auxin deficiency), the cell forms a double layer membrane vesicle, the cell autophago (autophagosomes), and simultaneously captures the damaged organelles (such as mitochondria, endoplasmic reticulum) and denatured proteins in the cells. In addition, the vesicles dissolve with lysosomes to form autophagic lysosomes (autolysosomes). Under the action of lysosomal hydrolase, the various organelles and biological macromolecules contained in the autophagosome can be digested and degraded to provide raw materials and energy for the resynthesis of new biological macromolecules. Therefore, autophagy is the machine. An important self-regulation and protection mechanism for maintaining internal homeostasis (homeostasis) and adapting to microenvironment changes. However, under certain conditions, excessive consumption of organelles and various biological macromolecules will eventually lead to another programmed cell death, cell autophagy death (autophagic cell death). A growing number of studies have shown that autophagy plays a very important role in the pathogenesis of immune, infection, inflammation, cancer, cardiovascular disease, and neurodegenerative disease. However, there are few studies on the cell autophagy in the respiratory system. The study elucidates the important regulatory role of autophagy in smoking induced airway epithelial cell injury and the formation of chronic obstructive pulmonary disease (COPD). However, the role of autophagy in the molecular pathogenesis of bronchial asthma is rarely reported.
Rapamycin (rapamycin) is a classic cell autophagy inducer, a macrolide antibiotic extracted from Streptomyces bibula on the Canadian Easter island in 1975. The main target of rapamycin, the mammalian mammalian target of rapamycin, mTOR, can accept and integrate growth factors, energy, and oxygen. The four major signals of gas and amino acids are involved in regulating energy metabolism, protein, lipid, synthesis of organelles and cell autophagy, which play an important regulatory role in cell growth, proliferation, differentiation and apoptosis, thus maintaining the homeostasis of the body and cells. The study of rapamycin in the animal model of asthma has been found. It is not consistent with reports that rapamycin can inhibit allergic airway inflammation, airway hyperresponsiveness, goblet cell production and IgE production, but some studies have also found that rapamycin has no effect on allergic airway inflammation and airway hyperresponsiveness. However, the key is that these studies only simply use rapamycin in vivo intervention. The observation of asthma phenotype did not clarify the key regulatory role of rapamycin and mTOR in the pathogenesis of asthma and its specific mechanism.
More and more studies have found that autophagy and mTOR play an important role in the differentiation and proliferation of hematopoietic stem cells. Autophagy can inhibit red blood hematopoiesis to cause severe anemia, inhibit the number and function of T lymphocytes, B lymphocytes, and mTOR by regulating T cell differentiation, function, metabolite and adaptive immune response. Cellular autophagy and mTOR are also involved in the regulation of bone marrow granulocyte progenitor cells, especially eosinophil differentiation, and further explore its possible role and contribution in the overall asthma model which is the main manifestation of eosinophil airway inflammation, thus developing a new field of vision for the study of the pathogenesis of asthma and preventing the clinical prevention of asthma. The treatment provides new targets.
This experiment is divided into two parts: (1) to explore the role of rapamycin and mTOR in airway inflammation and bone marrow eosinophil differentiation in asthma. (2) the use of Beclin1+/- and bone marrow transplantation in autophagy related gene knockout mice to elucidate cell autophagy in airway epithelial cell damage and bone marrow eosinophil differentiation, respectively. Different regulatory functions.
Part one effect of rapamycin on airway inflammation and eosinophil differentiation in asthmatic rats
Objective: To study the effect of rapamycin on airway inflammation in asthma and to explore the role of rapamycin in the regulation of T cell immune response and bone marrow eosinophil differentiation induced by OVA in lung tissue.
Methods: healthy female C57BL/6 mice were randomly divided into four groups: normal saline control group (group SHAM), model group (group OVA), rapamycin control group (group SHAM+RAPA), rapamycin asthma group (group OVA+RAPA). Asthma model was established with albumin (OVA) sensitization and stimulation, and saline control group replaced OVA with equal dose of saline in saline control group. Mycophenin group was injected intraperitoneally at 1 hours before each antigen excitation (1mg/kg). Pulmonary alveolar lavage fluid (BALF), eosinophil number in peripheral blood and bone marrow were detected at 24 hours after the last antigen excitation. The infiltration of airway inflammatory cells was observed by pathological sections of lung tissue, and IL-5 and IL-13 levels in serum were detected by ELISA. Flow cytometry And analyze the proportion of Th2, Th17, Treg T cell subsets in lung tissue, and detect the proportion of EoP (Lin-Sca-l-CD34+IL-5Ra+c-Kitl0) in bone marrow,.Western blot to detect the change of mTOR level during the differentiation of bone marrow eosinophils. In vitro cloning and formation test and bone marrow Eos induced differentiation and differentiation of rapamycin The effect of intervention on the differentiation and function of bone marrow eosinophils. Finally, using IL-5 transgenic mice NJ.1638, the number of eosinophils in peripheral blood and bone marrow was detected by intraperitoneal injection of rapamycin for 3 days. The level of IL-5 in serum was detected by ELISA, the proportion of EoP in bone marrow by flow cytometry and apoptosis of eosinophils were detected by flow cytometry.
Results: rapamycin induced OVA induced airway anaphylaxis significantly, but did not affect Th2 cells, Th17 cells and Treg levels in the lung tissue. Rapamycin inhibited the local and peripheral blood of the airway, the number of eosinophils in the bone marrow, but did not change the serum IL-5 level. In vitro cloning and formation test and bone marrow Eos induction. In vitro culture, rapamycin can directly inhibit the differentiation of IL-5 mediated eosinophils and the level of Eos secretion of IL-6 and IL-13 in supernatant. In vitro bone marrow cloning test and bone marrow flow cytometry results suggest that the inhibition of rapamycin on eosinophil differentiation eventually leads to bone marrow eosinophil progenitor cells The study of NJ.1638 in IL-5 transgenic mice also confirmed the inhibitory effect of rapamycin on the number of peripheral blood and bone marrow eosinophils and the aggregation of bone marrow EoP, which did not depend on the changes in the level of the serum high expression of IL-5, and did not affect the apoptosis of eosinophils.
Conclusion: rapamycin can alleviate the airway allergic inflammation in asthmatic mice, possibly by inhibiting the differentiation and function of bone marrow eosinophils, but has no obvious effect on the apoptosis of Eos and the immunity of T cells in the lung tissue.
The second part is the role of autophagy in airway inflammation and eosinophil differentiation in asthma.
Objective: To investigate the effect of autophagy knockout on the overall model of asthma, and to explore the different regulatory effects of autophagy on OVA induced airway epithelial cell damage and bone marrow eosinophil differentiation.
Methods: the changes of autophagy in the bone marrow and eosinophil induced differentiation of asthmatic mice were detected by Western blot, and the level of eosinophils in peripheral blood and bone marrow was analyzed by Swiss Giemsa staining, and the eosinophilia of bone marrow was detected by flow cytometry. The level of granulocyte progenitor cells and the ability to detect the differentiation of bone marrow eosinophils by the methyl cellulose clone formation test. At the same time, the asthma model was established by using Beclin1+/- mice and the same nest WT mice with OVA sensitization and stimulation. The random groups were as follows: the wild type physiological saline group (WT/NS), the wild type asthma model group (WT/OVA), Bec Lin1+/- mice in normal saline control group (BECN/NS) and Beclin1+/- mice asthma model group (BECN/OVA). 24 hours after the last stimulation, the airway responsiveness of mice was measured by invasive method, and the total number of leukocytes and eosinophils in the airway lavage fluid were detected. The infiltration of airway inflammatory cells and mucus secretion were observed in the lung tissue section. The aggregation of autophagic vesicles in airway epithelial cells of asthmatic mice was observed by electron microscopy. Normal lung epithelial cells (BEAS-2B) were cultured in vitro. Western blot was used to detect the change of autophagy during the intervention of OVA in vitro. Q-PCR was used to detect the expression of autophagy induced by starvation and IL-13 in vitro intervention on mucin MUC5AC mRNA. Finally, the method of bone marrow transplantation was used. The bone marrow hematopoietic system of wild type mice was damaged by combined chemotherapy of nitrosamines and cyclophosphamide, then the bone marrow of Beclin1+/- mice or the same fossa wild type mice was transplanted into the wild type mice and the hematopoietic system was rebuilt. The asthma model was induced by OVA, and the autophagy of the bone marrow was observed in two groups: group WT-WT-OVA and BECN-WT-OVA. Knockout contributes to airway hyperresponsiveness and airway inflammation in the overall asthma model.
Results: the number of eosinophils in peripheral blood and bone marrow was significantly increased and the level of bone marrow EoP decreased, but there was no significant difference in the number of eosinophils in the peripheral blood and bone marrow in mice with autophagy related gene knockout Beclin1+/- mice. The changes in the level of LC3B protein in the process of Eos induced differentiation in vitro suggest that the autophagy is involved in the bone marrow eosinophilia. In vitro clone formation test directly confirmed that the ability of Beclin1+/- mouse bone marrow eosinophil clone formation unit increased. However, the airway reactivity, airway inflammation and mucus hypersecretion of Beclin1+/- mice were not deteriorated compared with the wild type mouse model group. However, the LC3B protein level in the bone marrow of the asthmatic mice decreased, but the electron microscope showed that there was a cell autophagic vesicle aggregation in the bronchial epithelial cells of asthma. In vitro experiments showed that OVA intervention could increase the level of LC3B protein. The expression of MUC5AC mRNA in BEAS-2B cells mediated by IL-13 was further enhanced by starvation induced autophagy. In the bone marrow transplantation experiment, Beclin1+/ "is small. Airway inflammation and airway inflammation were significantly higher in asthmatic mice (BECN-WT-OVA group) than those in wild type mice (WT-WT-OVA group).
Conclusion: Although autophagy knockout in the animal model can alleviate airway allergic inflammation, airway hyperresponsiveness and mucus hypersecretion, there may be two completely opposite regulatory mechanisms in the process of airway local injury and bone marrow Eos differentiation. Autophagic knockout inhibits the OVA induced airway. Our study suggests that the study of autophagy and mTOR signaling pathways may provide a new approach to the prevention and treatment of asthma.

【學位授予單位】：浙江大學
【學位級別】：博士
【學位授予年份】：2013
【分類號】：R562.25

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