本文關(guān)鍵詞：細(xì)菌內(nèi)毒素耐受小鼠的細(xì)胞凋亡及信號轉(zhuǎn)導(dǎo)相關(guān)分子研究　出處：《第二軍醫(yī)大學(xué)》2006年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 內(nèi)毒素 耐受 細(xì)胞凋亡 信號分子

【摘要】：內(nèi)毒素(endotoxin)是革蘭氏陰性細(xì)菌(GNB)細(xì)胞壁外膜層的主要組成成分,其主要組成成分是脂多糖(LPS)。由親水性的多糖(O-特異性多糖、核心多糖)和疏水性的類脂A(Lipid A)組成。其中Lipid A是LPS中最為保守的部分,無種屬特異性,是LPS的主要生物活性成分。研究發(fā)現(xiàn)Lipid A結(jié)構(gòu)的完整性與LPS的毒性相關(guān)。LPS在細(xì)菌生長繁殖、死亡破裂或人工方法裂解后釋放。一旦進(jìn)入人或其他敏感動物體內(nèi),將對宿主各系統(tǒng)、器官產(chǎn)生廣泛影響。LPS不僅是決定GNB感染(如膿毒癥和感染性休克)的主要致病因子,而且與人類其他許多疾病關(guān)系密切,是一種危及人類健康乃至生命的最為重要的病原相關(guān)模式分子(PAMPs)。隨著有創(chuàng)技術(shù)、免疫抑制劑、細(xì)胞毒化療,以及廣譜抗生素使用的增多,膿毒癥和感染性休克的發(fā)病率自20世紀(jì)50年代以來一直呈增多趨勢,在美國每年因其死亡的人數(shù)達(dá)近20萬,兒童膿毒癥病死率為10%-15%,成人則高達(dá)40%。我國還沒有此方面的詳細(xì)報(bào)道。內(nèi)毒素的致病機(jī)制主要是LPS通過持續(xù)刺激機(jī)體單核巨噬細(xì)胞系統(tǒng),使之產(chǎn)生大量的細(xì)胞因子,包括TNF-α,IL-6,IL-12等,活性氧、溶酶體酶、NO等活性物質(zhì),引起細(xì)胞損傷和凋亡,最終導(dǎo)致失控性炎癥反應(yīng),并伴有較高的機(jī)體死亡率。 盡管宿主細(xì)胞在細(xì)菌產(chǎn)物的作用下出現(xiàn)以細(xì)胞凋亡為特征的細(xì)胞死亡現(xiàn)象,但是宿主在細(xì)菌致病產(chǎn)物的作用下并非總是被動的。他們積極主動的調(diào)動宿主抗御死亡的機(jī)制來對抗細(xì)菌的攻擊,降低并緩解細(xì)菌對宿主的損害程度。當(dāng)宿主多次接觸細(xì)菌內(nèi)毒素,再次給予高劑量的細(xì)菌內(nèi)毒素時(shí),宿主僅出現(xiàn)輕微的反應(yīng)或不反應(yīng),這種現(xiàn)象被定義為內(nèi)毒素耐受或稱之為低應(yīng)答(hyporesponsiveness),它被認(rèn)為是機(jī)體的一種適應(yīng)性反應(yīng),可以有效的抑制單核巨噬細(xì)胞過度表達(dá)引起的炎癥反應(yīng)及敗血癥休克。 內(nèi)毒素耐受現(xiàn)象一個(gè)世紀(jì)前就已經(jīng)被認(rèn)識到,但其作用機(jī)制至今尚未研究清楚,而且內(nèi)毒素耐受的出現(xiàn)與細(xì)胞凋亡的抑制是否有關(guān),也是一個(gè)倍受關(guān)注的問題。因此,本研究首先誘導(dǎo)小鼠出現(xiàn)內(nèi)毒素耐受現(xiàn)象,檢測耐受后的小鼠的肝組織細(xì)胞中是否出現(xiàn)凋亡現(xiàn)象。在此基礎(chǔ)上,我們探討了耐受現(xiàn)象與細(xì)胞凋亡及機(jī)體死亡之間的關(guān)系。研究在耐受出現(xiàn)后,動物組織細(xì)胞中凋亡相關(guān)信號分子及LPS相關(guān)信號分子的變化。 一、小鼠內(nèi)毒素耐受模型的建立
[Abstract]:Endotoxin (endotoxin) is a major component of the outer membrane of the cell wall of Gram-negative bacteria (GNB). Its main component is lipopolysaccharide (LPS). Core polysaccharides) and hydrophobic lipopolipid A). Lipid A is the most conserved part of LPS and has no species specificity. It is found that the integrity of Lipid A structure is related to the toxicity of LPS. Death ruptures or artificial cleavage after release. Once entered into humans or other sensitive animals, the host system will be affected. LPs is not only the main pathogenic factor in determining GNB infection (such as sepsis and septic shock), but also closely related to many other human diseases. It is one of the most important pathogen-related model molecules that endanger human health and even life. With the increase of invasive technology, immunosuppressant, cytotoxic chemotherapy, and the use of broad-spectrum antibiotics. The incidence of sepsis and septic shock has been increasing since 1950s. In the United States, the number of deaths per year is nearly 200,000, and the mortality of children with sepsis is 10-15%. The pathogenic mechanism of endotoxin is that LPS continuously stimulates the mononuclear macrophage system to produce a large number of cytokines. Including TNF- 偽, IL-6, IL-12, reactive oxygen species, lysosomal enzyme no and other active substances, resulting in cell damage and apoptosis, eventually leading to uncontrolled inflammatory response. With higher body mortality. Although the host cells under the action of bacterial products, cell death characterized by cell apoptosis. But the host is not always passive under the action of the bacterial pathogenic product. They actively mobilize the host to resist the death mechanism to resist the bacterial attack. Reduce and alleviate the degree of bacterial damage to the host. When the host is exposed to bacterial endotoxin for several times and given a high dose of bacterial endotoxin again, the host has only a slight or no reaction. This phenomenon is defined as endotoxin tolerance or hyporesponsiveness, which is considered to be an adaptive response of the body. It can effectively inhibit the inflammatory response and septicemia shock caused by the excessive expression of mononuclear macrophages. The phenomenon of endotoxin tolerance has been recognized a century ago, but the mechanism of endotoxin tolerance has not been studied, and whether the occurrence of endotoxin tolerance is related to the inhibition of apoptosis. Therefore, this study first induced the phenomenon of endotoxin tolerance in mice, and detected whether there was apoptosis in the liver tissue cells of mice after tolerance. We investigated the relationship between tolerance, apoptosis and death, and studied the changes of apoptosis-related signaling molecules and LPS related signaling molecules in animal tissue cells after tolerance. 1. Establishment of mouse endotoxin tolerance model
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2006
【分類號】：R363

【參考文獻(xiàn)】

相關(guān)期刊論文 前3條

1 高娟,李康樗,葉菁,李青;Fas和TNFR1介導(dǎo)凋亡途徑中的相關(guān)蛋白[J];國外醫(yī)學(xué)(生理、病理科學(xué)與臨床分冊);2000年05期

2 李崇輝,劉巨超,藏傳波,陳明易,吳榮謙,徐迎新,黃志強(qiáng);巨噬細(xì)胞內(nèi)毒素耐受時(shí)TLR4/MD-2的基因表達(dá)調(diào)節(jié)作用[J];中華實(shí)驗(yàn)外科雜志;2004年01期

3 Marina Gumenscheimer;Marina A. Freudenberg;Chris Galanos;;Lethal effect and apoptotic DNA fragmentation in response of D-GalN-treated mice to bacterial LPS can be suppressed by pre-exposure to minute amount of bacterial LPS: Dual role of TNF receptor 1[J];World Journal of Gastroenterology;2005年22期

，

本文編號：1369572