發(fā)布時間：2018-05-20 05:43

  本文選題：多糖 + 對人�。� 參考：《武漢大學》2016年博士論文

【摘要】：背景：滑膜炎是一種常見病,多發(fā)病,其病程長,類型多,且容易反復發(fā)作,患者出現關節(jié)腫痛,活動受限,嚴重影響日常生活。尤其以細菌性滑膜炎,類風濕性滑膜炎為著,難以治愈。臨床以無菌性滑膜炎多見,滑膜炎是關節(jié)炎的早期癥狀,人類關節(jié)滑膜為疏松結締組織,可分為兩層：滑膜襯里層和滑膜襯里下層�；ひr里層是由具有巨噬細胞樣功能的A型細胞及纖維母細胞樣的B型細胞組成,而襯里下層是由疏松結締組織基質構成,與其深層的纖維細胞并無基底膜相隔,直接與纖維結締組織或脂肪組織相連接,故在關節(jié)發(fā)生炎癥時易蔓延到周圍組織,導致滑膜炎的發(fā)生。人體中包含多個關節(jié),滑膜炎可發(fā)生在全身各個關節(jié)之中。其中,膝關節(jié)具有特殊的解剖結構,是全身關節(jié)中滑膜最多的關節(jié)。而且,膝關節(jié)容易受到外力等的影響而出現損傷。因此,在臨床中,滑膜炎大多以膝關節(jié)最為多見。而滑膜炎一旦出現,如果治療不及時,就遷延成慢性膝關節(jié)滑膜炎�；颊叩南リP節(jié)便會逐漸呈現出腫脹和疼痛等癥狀,長此以往,就會對患者的膝關節(jié)功能產生嚴重的影響,導致功能障礙的出現,嚴重影響患者的日常生活和工作�；ぱ资窃缙诠顷P節(jié)炎(Osteoarthritis, OA)中常見的癥狀之一,被大家認為是炎癥反應。它主要是由炎性因子和促炎性因子導致滑膜的炎癥反應和關節(jié)軟骨破壞的不平衡產生的。在長期的致病因素作用下,導致滑膜增生并逐漸增厚,與此同時纖維層和細胞層被嵌入,血管增生。由于炎性細胞浸潤與滑膜成纖維細胞的增生,導致滑膜毛細血管在滑膜和滑液中選擇性分布,從而使關節(jié)遭到進一步破壞�；ぱ捉M織病理學表現為滑膜組織急性期充血,水腫,中性粒細胞和大量炎性細胞浸潤,滑膜血管擴張,血漿和細胞外滲產生大量滲出液,滑膜細胞活躍,產生大量粘液素。慢性期病變的滑膜組織表現出明顯的血管增生和炎癥細胞浸潤。在初步的流行病學調查中表明,膝關節(jié)骨性關節(jié)炎的患病率為60%,56歲及以上的患病率為49%。女性比男性更常見�；加泄顷P節(jié)炎患者更易發(fā)生滑膜炎疾病,滑膜炎同時加重骨關節(jié)炎的發(fā)生。由滑膜細胞因子,蛋白酶和前列腺素分泌的炎性細胞如PGE的活化直接參與關節(jié)軟骨的病損�；ぱ资荗A軟骨改變功能的早期表現,促進血管增生,異常的骨周轉率,從而嚴重損害關節(jié)結構�；ず蛙浌窃谒械慕佑|口都有不同程度的軟骨糜爛,光學顯微鏡下可以看到,滑膜軟骨生長侵蝕。關節(jié)軟骨的破壞,除了機械原因之外,細胞因子也起著關鍵的作用。主要是滑膜炎導致的IL-1分泌的增加,和金屬蛋白酶的分泌及活性增加,引起軟骨破壞。同時滑膜炎也是類風濕性關節(jié)炎(Rheumatoid arthritis, RA)主要病理學表現。與其他慢性疾病相比,類風濕關節(jié)炎的早期診斷率較低。此外,國外學者發(fā)現,類風濕性關節(jié)炎患者的預期壽命也相對較短。因為它的高致殘率,使社會的經濟負擔逐年上升,RA已成為必須注意的一個公共衛(wèi)生問題。但不幸的是,對RA的發(fā)病機理,目前的研究還不是很透徹明了,在以往對滑膜炎的發(fā)生發(fā)展及治療過程的研究中發(fā)現,滑膜組織中存在的三種絲裂原活化蛋白激酶(MAPK)信號轉導通路,即細胞外調節(jié)蛋白激酶(ERK)信號轉導通路,P38絲裂原活化蛋白激酶MAPK信號轉導通路,C-jun氨基末端激酶信號轉導通路。以上信號轉導通路與滑膜炎的發(fā)生發(fā)展存在密切聯系。絲裂原活化蛋白激酶(MAPK)是真核生物信號傳遞網絡的重要組成部分,可以參與到細胞質功能活動以及基因表達調控等多項活動中,并發(fā)揮十分重要的作用。是細胞內廣泛表達的絲氨酸／蘇氨酸的蛋白激酶被磷酸化激活后,參與細胞的生長、發(fā)育、分化、凋亡等一系列細胞生理活動,主要包括JNK,ERK,P38三條信號轉導通路。研究表明,絲裂原活化蛋白激酶(MAPK)能夠影響滑膜炎的發(fā)生發(fā)展。MAPK通路是一種信號轉導酶系統(tǒng),在受到一定應激刺激之后,細胞內部系統(tǒng)便會利用這一信號通路做出一定的反應。而一旦這一信號通路發(fā)生異常變化,導致傳導異常,并容易導致滑膜炎的出現。受到一些特定細胞因子或者抗原的影響,MAPK可以通過相應的信號轉導系統(tǒng),進入到細胞核之中,啟動一系列行為的出現。但是,在發(fā)生異常的增殖之后,滑膜細胞的轉錄因子便會出現改變。這些轉錄活化因子的活性均與MAPK信號轉導通路相關,受到其調控。在細胞異常增殖的情況下,會導致大量促炎性細胞因子等的分泌。進而導致滑膜細胞發(fā)生異常改變,導致其出現增生和肥厚等情況。脂多糖(Lipopolysaccharide, LPS)是革蘭氏陰性細菌細胞壁的具體結構。是內毒素的主要成分,脂多糖由核心多糖,O多糖側鏈和脂質A組成,脂多糖可以通過絲裂原活化蛋白激酶MAPK信號通路作用于滑膜細胞,在一定條件下,革蘭氏陰性菌活菌可以緩慢釋放少量LPS,死亡后大量釋放LPS,革蘭氏陰性細菌感染可引起患者的血漿中的LPS水平顯著增加。也可以提高所引起的局部相繼感染的LPS水平。根據先前的研究中,在患有革蘭氏陰性細菌性陰道炎的婦女宮頸中,可以檢測到比較高水平的LPS。并且在研究中發(fā)現,LPS可以通過絲裂原活化蛋白激酶MAPK信號通路抑制滑膜細胞的生長,其可以誘導滑膜炎的發(fā)生發(fā)展。脂多糖濃度與滑膜炎滑液中誘導型一氧化氮合酶表達成正相關,其與炎性因子相互作用加重滑膜炎程度。這一作用是通過滑膜組織中存在的絲裂原活化蛋白激酶(MAPK)轉導通路實現的。目的：本研究以滑膜細胞為研究對象,用LPS作用滑膜細胞,尋找到LPS對滑膜細胞生長的MAPK通路的作用機制。以至為進一步研究MAPK通路蛋白在滑膜炎的發(fā)生和發(fā)展過程中存在的重要作用,以期找到新的治療靶點,為制定有效治療滑膜炎方案奠定基礎。方法：用不同濃度的LPS作用滑膜細胞,然后用MTT和流式細胞儀檢測在不同時間的滑膜細胞的增長情況,找到LPS對滑膜細胞生長的最佳作用時間與濃度。通過用LPS作用于HS細胞,在不同時間收集細胞,提取蛋白,用Western blot的方法檢測MAPK通路中的關鍵蛋白ERK,JNK,p38的磷酸化狀況,從而確定其激活蛋白。然后用相應的蛋白酶激動劑作用磷酸化的關鍵蛋白,檢測細胞的生長情況及下游的蛋白活化情況。為了進一步研究LPS的作用機制,將LPS的受體TRL4用RNA干擾的方法進行抑制,然后檢測蛋白ERK,JNK,p38的磷酸化狀況及細胞的生長情況。結果：(1)用MTT法檢測了0,10,20和40ng/ml的LPS作用于人滑膜細胞后于第0,24,48和72h計算生長率,當加入LPS后從24h開始,其生長率逐漸降低。在10ng/ml組中細胞的生長率隨著時間的增加而降低,但沒有20和40ng/ml組降低明顯。在20ng/ml和40ng/ml組中其生長情況相似。采用Annexin V/PI流式細胞分析法進行了凋亡率的定量研究,檢測HS細胞0,10ng/ml,20ng/ml,40ng/ml的LPS處理后的凋亡率。不同濃度LPS處理HS細胞后,能誘導HS細胞發(fā)生凋亡誘導作用,且凋亡率隨LPS濃度的增加而增加,當LPS濃度為20ng/ml時,細胞凋亡率達到極值,值后不再變化。這就表明20ng/ml的LPS在48h時對HS細胞的生長率抑制情況最佳為24.0340.3 1%。(2)在本研究中用總濃度為20ng/ml的LPS作用于HS細胞磷酸化JNK(p-JNK)的條帶隨著時間的增加表達量越來越低,而非磷酸化的JNK(T-JNK)條帶在各個時間的表達基本一致。對于P-ERK和T-ERK的條帶在各個時間的表達也基本一致。而p-p38的條帶在各個時間都很淺幾乎看不清。而T-p38的條帶則很均一且很深。這就表明LPS對HS細胞生長的抑制作用是通過抑制磷酸化JNK來實現的。而且在LPS作用40min時已經發(fā)揮到極致。為了進一步證明LPS對HS細胞生長的抑制作用是通過JNK通路實現的,采用了JNK的激動劑anisomycin作用于HS細胞,同時加入LPS來證明磷酸化的JNK蛋白情況,以及JNK下游蛋白磷酸化的ATF-2情況。結果表明當加入Anisomycin時,對P-ATF-2/ATF-2的值從一開始到60min均沒有明顯變化,且表達值較高(P0.05).同時研究了當加入Anisomycin后,細胞的生長情況,細胞的生長速度較快從一開始的85.19%長到了第六天的96.52%,在這六天中細胞始終保持較高的生長速度。(3)提取HS的RNA并進行了充分TLR4的RT-PCR實驗,然后將PCR產物進行1%的瓊脂糖凝膠電泳,在成像系統(tǒng)中可以看到TLR4的表達條帶。表明了TLR4在核酸水平上游表達。為進一步證明TLR4的表達,提取了HS的蛋白,進行了Western blot實驗。結果同樣表明TLR4在HS細胞中有表達。利用RNA干擾技術將TLR4沉默。同時應用PCR技術和Western blot技術驗證了TLR4被成功沉默。同時還篩選出了TLR4敲除的細胞系。用SiRNA的方法將TLR4干擾后,并經篩選后得到穩(wěn)定的細胞細胞系,然后,用MTT法檢測了用20ng/ml的LPS作用于HS細胞后,于第0,24,48和72h檢測細胞的生長情況,并計算細胞的生長率,在干擾組中(SiRNA+LPS組)細胞在此期間的生長呈增長趨勢,無顯著變化(P0.05)。而在對照組中(LPS組)細胞的生長率逐漸下降。TLR4被抑制后HS細胞中ERK,JNK,p38的磷酸化情況,本研究對蛋白進行了灰度值得分析,同時將對應的磷酸化蛋白與非磷酸化蛋白的灰度值相比,而后將所得值進行比較。無論是p-JNK/T-JNK還是p-ERK/T-ERK和P-P38/T-P38的值均未隨著時間的增加而變化,且p-JNK/T-JNK的值明顯低于TLR4未被抑制時的值。結論：總的來說,我們的結果表明LPS抑制HS的增長主要信號通路是通過MAPK通路中JNK通路途徑實現的。為進一步的研究MAPK通路蛋白在滑膜炎的發(fā)生和發(fā)展過程中存在的重要作用,找到新的治療靶點,制定有效治療滑膜炎方案奠定基礎。
[Abstract]:Background: synovitis is a common disease, frequently occurring disease, long course of disease, many types, and easy to relapse. The patients have joint swelling and pain, and their activities are limited, which seriously affect daily life. Especially, bacterial synovitis and rheumatoid synovitis are difficult to cure. Clinical symptoms of non bacterial synovitis are common, synovitis is an early symptom of arthritis. The synovium of the joint synovium is a loose connective tissue, which can be divided into two layers: the synovial lining and the underlining of the synovial lining. The synovial lining is composed of A type cells with macrophage like function and B cells like fibroblast like cells, and the underlayer of the lining is composed of loose connective tissue matrix and no basement membrane separated from its deep fibrous cells. Connecting with fibrous connective tissue or adipose tissue, it is easy to spread to the surrounding tissue during the joint inflammation, leading to the occurrence of synovitis. The body contains multiple joints and synovitis can occur among the various joints of the body. Among them, the knee joint has a special anatomical structure, the most synovial joint in the joint. In clinical, synovitis is most common in the knee joint. Once the synovitis occurs, if the treatment is not timely, the synovitis will be extended to chronic knee synovitis. The patient's knee joint will gradually show swelling and pain and other symptoms, in the long run, the knee joint will be on the patient's knee joint. Function has a serious effect that causes the appearance of dysfunction, which seriously affects the daily life and work of the patient. Synovitis is one of the common symptoms in Osteoarthritis (OA). It is considered to be an inflammatory reaction. It is mainly caused by inflammatory factors and proinflammatory factors leading to the inflammation of the synovial membrane and the destruction of the articular cartilage. The imbalance is produced. The synovial hyperplasia and thickening of the synovial membrane and the proliferation of the blood vessels are caused by the long-term pathogenic factors. The infiltration of inflammatory cells and the proliferation of the synovial fibroblasts can lead to the selective distribution of the synovial capillaries in the synovium and synovial fluid, thus causing the joint to be further broken. The histopathology of synovitis is characterized by hyperemia, edema, neutrophils and infiltration of inflammatory cells in the acute phase of synovitis, the dilatation of the synovial vessels, a large amount of exudation in plasma and cell exudation, the active synovial cells and a large number of mucin. The synovial tissue of chronic phase lesions shows obvious vascular proliferation and inflammatory cell infiltration. In a preliminary epidemiological survey, the prevalence of osteoarthritis of the knee is 60%, the prevalence rate of 56 years old and above is more common in 49%. women than in men. Patients with osteoarthritis are more likely to have synovitis, and synovitis aggravates osteoarthritis. The inflammatory properties of synovial cell factor, protease and prostaglandin secretion are more frequent. The activation of the cells, such as PGE, is directly involved in the lesion of articular cartilage. Synovitis is an early manifestation of the function of OA cartilage change, promoting vascular proliferation, abnormal bone turnover, and serious damage to the joint structure. Synovial and cartilage at all contacts have varying degrees of cartilage erosion. Under optical microscope, the synovial cartilage can be seen to invade cartilage. In addition to mechanical causes, cytokine also plays a key role in the destruction of articular cartilage. It is mainly the increase of IL-1 secretion caused by synovitis, and the increase of the secretion and activity of metalloproteinase, causing cartilage destruction. Meanwhile, synovitis is also the main pathological manifestation of Rheumatoid arthritis (RA). The early diagnosis rate of rheumatoid arthritis is lower than that of sexual diseases. In addition, foreign scholars have found that the life expectancy of patients with rheumatoid arthritis is also relatively short. Because of its high disability rate, the economic burden of the society is increasing year by year, and RA has become a public health problem that must be paid attention to. Unfortunately, the pathogenesis of RA is now at present. The study is not clear. In the previous study of the development and treatment of synovitis, three kinds of mitogen activated protein kinase (MAPK) signal transduction pathway in synovial tissue, namely, extracellular regulated protein kinase (ERK) signal transduction pathway, P38 mitogen activated protein kinase MAPK signal transduction pathway, C-jun The signal transduction pathway of the amino terminal kinase. The signal transduction pathway is closely related to the development of synovitis. Mitogen activated protein kinase (MAPK) is an important part of the eukaryotic signaling network. It can be involved in many activities, such as cytoplasmic functional activity and gene expression regulation, and plays a very important role. A series of cell physiological activities such as growth, development, differentiation and apoptosis are involved in cell growth, development, differentiation, and apoptosis, which mainly include JNK, ERK, and P38 three signal transduction pathways. The study shows that mitogen activated protein kinase (MAPK) can affect the occurrence and development of synovitis.MAP The K pathway is a signal transduction enzyme system. After a certain stress stimulation, the internal system of the cell can use this signal pathway to make a certain response. Once this signal pathway changes, it causes abnormal conduction and causes the occurrence of synovitis. It is affected by some specific cytokines or antigens, MAPK The transcriptional factors of the synovial cells change after the abnormal proliferation, and the activity of these activators is related to the MAPK signal transduction pathway and is regulated by its regulation. In the case of abnormal cell proliferation, the activity of the transcription activator is regulated by the signal transduction pathway. Lipopolysaccharide (LPS) is the specific structure of the cell wall of Gram-negative bacteria. It is the main component of the endotoxin, and the lipopolysaccharide is composed of the core polysaccharide, the O polysaccharide side chain and the lipid A. Lipopolysaccharide can act on the synovial cells through the mitogen activated protein kinase MAPK signaling pathway. Under certain conditions, Gram-negative bacteria can release a small amount of LPS slowly and release a large amount of LPS after death. The gram negative bacterial infection can cause a significant increase in the level of LPS in the plasma of the patient. The LPS level of infection. According to previous studies, a higher level of LPS. can be detected in the cervix of women with gram-negative bacterial vaginitis and in the study, LPS can inhibit the growth of synoviocytes through the mitogen activated protein kinase MAPK signaling pathway, which can induce the development of synovitis. The concentration of polysaccharides is positively related to the expression of inducible nitric oxide synthase in synovitis and synovitis, and its interaction with inflammatory factors aggravates the degree of synovitis. This effect is achieved through the mitogen activated protein kinase (MAPK) transduction pathway in the synovial tissue. Objective: This study was based on synovial cells and used LPS as a synovial membrane. Cells, looking for the mechanism of the action of LPS on the MAPK pathway of synovial cell growth, so as to further study the important role of MAPK pathway protein in the occurrence and development of synovitis, in order to find new therapeutic targets and lay the foundation for the formulation of effective treatment scheme for synovitis. Methods: Using different concentrations of LPS in synovial cells, Then MTT and flow cytometry were used to detect the growth of synovial cells at different time and to find the best time and concentration of LPS on the growth of synovial cells. By using LPS to act on HS cells, the cells were collected at different time and the protein was extracted. The key protein ERK, JNK, p38 in the MAPK pathway was detected by Western blot. In order to determine the activation protein, then use the corresponding protease agonist to act as the key protein of phosphorylation, detect the cell growth and the downstream protein activation. In order to further study the mechanism of the action of LPS, the LPS receptor TRL4 is suppressed by RNA interference, and then the phosphorylation status of protein ERK, JNK, p38 is detected. Results: (1) the growth rate of 0,10,20 and 40ng/ml LPS in human synovial cells was measured in 0,24,48 and 72h by MTT method. When LPS was added to LPS, the growth rate decreased gradually. In the 10ng/ml group, the growth rate of cells decreased with the increase of time, but no 20 and 40ng/ml groups decreased obviously. In 2 The growth of 0ng/ml and 40ng/ml group was similar. The apoptosis rate was quantified by Annexin V/PI flow cytometry. The apoptotic rate after LPS treatment of 0,10ng/ml, 20ng/ml, 40ng/ml in HS cells was detected. The apoptosis induction of HS cells could be induced by the treatment of HS cells with different concentrations of LPS, and the apoptosis rate increased with the increase of concentration. Adding, when the concentration of LPS is 20ng/ml, the cell apoptosis rate reaches the extreme value and no longer changes. This indicates that the optimal growth rate of 20ng/ml LPS at 48h is 24.0340.3 1%. (2) in this study, LPS with the total concentration of 20ng/ml is used in HS cell phosphorylation JNK. The low, non phosphorylated JNK (T-JNK) bands were basically the same at all time. The bands of the P-ERK and T-ERK bands were almost identical at all time. And the bands of p-p38 were very shallow at every time. And the bands of T-p38 were very homogeneous and very deep. This shows that the inhibition of LPS to HS cell growth is by inhibiting the growth of HS cells. In order to further prove that the inhibitory effect of LPS on HS cell growth is realized by the JNK pathway, the activator anisomycin of JNK acts on HS cells, and LPS is added to prove the JNK protein of phosphorylation, and the phosphorylation of downstream JNK downstream proteins in order to further prove that the inhibitory effect of LPS on HS cell growth is achieved. The results showed that when Anisomycin was added, the value of P-ATF-2/ATF-2 was not significantly changed from the beginning to 60min, and the expression value was higher (P0.05). At the same time, the growth of cells was studied when Anisomycin was added, and the growth rate of the cells was faster from 85.19% to 96.52% in sixth days, and the cells were all the time in these six days. Keep high growth speed. (3) the RNA of HS was extracted and the RT-PCR experiment of full TLR4 was carried out. Then the PCR product was carried out by 1% agarose gel electrophoresis, and the expression strip of TLR4 could be seen in the imaging system. The expression of TLR4 in the upstream of nucleic acid was shown. To further prove the expression of TLR4, the HS protein was extracted, and Western blot was carried out. The results also showed that TLR4 was expressed in HS cells. TLR4 was silenced using RNA interference technique. Meanwhile, PCR and Western blot techniques were used to verify that TLR4 was successfully silenced. At the same time, TLR4 knockout cell lines were screened. TLR4 interfered with SiRNA, and stable cell lines were obtained after screening, and then, MTT method was used. The growth of cells in 0,24,48 and 72h cells was detected after the action of 20ng/ml's LPS on HS cells, and the growth rate of cells was calculated. The growth of cells in the interference group (group SiRNA+LPS) showed a growing trend in this period, without significant change (P0.05). The growth rate of the cells in the control group (LPS group) decreased gradually after the.TLR4 was suppressed by HS cells. The phosphorylation of ERK, JNK and p38 in this study is worth analyzing in this study. At the same time, the corresponding phosphorylated protein is compared with the gray value of the non phosphorylated protein, and then the values are compared. Both the values of p-JNK/T-JNK and p-ERK/T-ERK and P-P38/T-P38 have not changed with the time, and the value of p-JNK/T-JNK. It is significantly lower than the value of TLR4 that is not suppressed. Conclusion: Overall, our results show that the main signal pathway of the growth of LPS inhibition HS is achieved through the JNK pathway in the MAPK pathway. To further study the important role of MAPK pathway protein in the occurrence and development of synovitis, find new therapeutic targets and formulate a new therapeutic target. It lays the foundation for the scheme of effective treatment of synovitis.
【學位授予單位】：武漢大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R686.7

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