本文選題：內(nèi)毒素血癥 + 脂多糖��； 參考：《重慶醫(yī)科大學(xué)》2011年博士論文

【摘要】：背景與目的膿毒癥是嚴(yán)重感染、創(chuàng)傷、燒傷、外科大手術(shù)患者常見的并發(fā)癥,進(jìn)一步發(fā)展可導(dǎo)致膿毒癥休克和多器官功能障礙綜合征(MODS),是臨床危重患者死亡的最主要原因之一。全球膿毒癥患者總病例數(shù)約為1800萬/年,美國患病人數(shù)為75萬/年,歐洲為13.5萬/年。全世界死亡人數(shù)超過1.4萬/天,美國21.5萬/年,并成為美國非心臟ICU死亡的主因。目前對膿毒癥的認(rèn)識及治療措施有所改進(jìn),但膿毒癥的病死率仍然居高不下,已成為現(xiàn)代危重病醫(yī)學(xué)面臨的突出難題。根本原因源于膿毒癥的根本發(fā)病環(huán)節(jié)及作用機(jī)制尚未充分闡明,故而缺乏早期有效的預(yù)防與治療措施。 失控的全身炎癥反應(yīng)是膿毒癥預(yù)后不良的重要原因之一。固有免疫細(xì)胞是炎癥反應(yīng)的重要參與者,其異�；罨蓪�(dǎo)致失控炎癥反應(yīng)的發(fā)生。感染相關(guān)的噬血細(xì)胞綜合征(IAHS)及重癥急性呼吸道綜合征(SARS)、重癥H1N1等高致死性流行病毒感染性疾病,其病理生理特點(diǎn)亦為失控的全身炎癥反應(yīng)綜合征。以上疾病存在著固有免疫細(xì)胞的異�；罨�,是疾病發(fā)生的重要原因之一,但對于何種原因?qū)е鹿逃忻庖呒?xì)胞的異�；罨枰M(jìn)一步研究。近年的研究顯示了固有免疫細(xì)胞與適應(yīng)性免疫細(xì)胞在炎癥反應(yīng)中相互作用的復(fù)雜性。我們的前期研究顯示T細(xì)胞缺陷裸鼠感染呼吸道合胞病毒(RSV)后,炎癥反應(yīng)重于野生型小鼠,提示T細(xì)胞可能抑制炎癥反應(yīng)發(fā)生。Kim的研究顯示炎癥早期,淋巴細(xì)胞可抑制固有免疫細(xì)胞活化。由此,我們推測,膿毒癥,IAHS及SARS等的發(fā)生可能與機(jī)體體內(nèi)淋巴細(xì)胞不同程度功能缺陷導(dǎo)致固有免疫細(xì)胞異�；罨嚓P(guān)。若能對淋巴細(xì)胞缺陷動物膿毒癥中固有免疫細(xì)胞活化及功能特征進(jìn)行研究,也許能為以上疾病的發(fā)病環(huán)節(jié)及作用機(jī)制研究提供新的思路。 內(nèi)毒素在革蘭陰性細(xì)菌感染所致膿毒癥的發(fā)病機(jī)制中扮演重要作用,甚至細(xì)菌血培養(yǎng)陰性時,也存在內(nèi)毒素血癥,提示內(nèi)毒素血癥可是膿毒血癥的單獨(dú)致病因素。內(nèi)毒素具有極廣泛而又復(fù)雜的生物學(xué)效應(yīng),膿毒癥病理過程中出現(xiàn)的失控炎癥反應(yīng)、免疫機(jī)能紊亂、高代謝狀態(tài)及多臟器功能損害均可由內(nèi)毒素直接或間接觸發(fā)。淋巴細(xì)胞缺陷的重癥聯(lián)合免疫缺陷(SCID)小鼠革蘭陰性細(xì)菌感染模型的病理性免疫反應(yīng)(炎癥反應(yīng))取決于細(xì)菌的持續(xù)繁殖擴(kuò)散和宿主的免疫反應(yīng)。這一模型給研究單一免疫反應(yīng)帶來困難。為避免此類情況的發(fā)生,我們擬采用脂多糖(LPS)腹腔注射誘導(dǎo)T、B細(xì)胞缺陷重癥聯(lián)合免疫缺陷小鼠內(nèi)毒素血癥,通過觀察SCID小鼠巨噬細(xì)胞生物學(xué)特性,從而揭示淋巴細(xì)胞缺陷對炎癥反應(yīng)的影響以及對巨噬細(xì)胞活化的調(diào)控作用及其作用可能的分子機(jī)制,為膿毒癥的防治提供新的方向和理論依據(jù)。 目的在LPS誘導(dǎo)的BALB/c小鼠和SCID小鼠內(nèi)毒素血癥模型基礎(chǔ)上,比較兩種小鼠炎癥反應(yīng)的差異,觀察淋巴細(xì)胞缺陷對固有免疫應(yīng)答及炎癥反應(yīng)的影響。 方法LPS腹腔注射BALB/c小鼠和SCID小鼠后,觀察小鼠的一般狀況及存活率。將32只雄性BALB/c小鼠和32只雄性SCID小鼠隨機(jī)分為正常對照組,LPS注射后3 h,6 h和12 h組。取小鼠的血清,肝臟及肺臟組織;用全自動生化分析儀檢測兩種小鼠血清谷丙轉(zhuǎn)氨酶(ALT)、谷草轉(zhuǎn)氨酶(AST)及血尿素氮(BUN)水平;用H.E染色,雙盲法評估肝臟,肺臟的炎癥病理損傷;用流式細(xì)胞術(shù)微球陣列法(CBA)檢測兩種小鼠血清TNF-α, IFN-γ, IL-10, IL-6及MCP-1的水平;用ELISA檢測兩種小鼠血清IL-12, IL-4及IL-17的水平及肝組織勻漿TNF-α及IL-10的水平。 結(jié)果LPS誘導(dǎo)內(nèi)毒素血癥后,SCID小鼠于12～24 h均死亡(8/8),BALB/c小鼠僅1只死亡(1/8);LPS注射后12 h,SCID小鼠血清ALT、AST均高于BALB/c小鼠,兩種小鼠BUN無顯著差異;SCID小鼠肝臟、肺臟病理評分均高于BALB/c小鼠;LPS注射后,兩種小鼠血清TNF-α,IFN-γ,IL-10,IL-6,MCP-1及IL-4的水平均顯著升高,且SCID小鼠以上細(xì)胞因子水平明顯高于BALB/c小鼠;LPS注射后3 h,SCID小鼠肝組織勻漿TNF-α水平高于BALB/c小鼠,注射后6 h,IL-10水平高于BALB/c小鼠。 結(jié)論LPS誘導(dǎo)小鼠內(nèi)毒素血癥后,與野生型BALB/c小鼠比較,SCID小鼠分泌過量的炎性及抗炎細(xì)胞因子,出現(xiàn)失控的炎癥反應(yīng),導(dǎo)致嚴(yán)重的臟器損傷,是SCID小鼠死亡的重要原因。固有免疫應(yīng)答在缺乏淋巴細(xì)胞的狀態(tài)下異常增強(qiáng),可能是發(fā)生危及生命的重癥全身炎癥反應(yīng)綜合征的重要原因。 第二部分脂多糖誘導(dǎo)的BALB/c小鼠與SCID小鼠內(nèi)毒素血癥腹腔巨噬細(xì)胞活化及功能的比較 目的在LPS誘導(dǎo)的BALB/c小鼠和SCID小鼠內(nèi)毒素血癥模型基礎(chǔ)上,比較BALB/c小鼠及SCID小鼠腹腔巨噬細(xì)胞活化及功能的差異。觀察淋巴細(xì)胞缺陷對巨噬細(xì)胞活化及功能的影響。 方法將40只雄性BALB/c小鼠和40只雄性SCID小鼠各自隨機(jī)分為正常對照組,LPS注射后1 h,3 h,6 h和12 h組。取小鼠的腹腔灌洗液,腹腔巨噬細(xì)胞和小鼠脾臟NK細(xì)胞;用ELISA檢測腹腔灌洗液TNF-α和IL-10的水平;用實(shí)時熒光定量PCR檢測腹腔巨噬細(xì)胞TNF-α和IL-10 mRNA表達(dá);流式細(xì)胞術(shù)檢測BALB/c小鼠及SCID小鼠正常對照組及LPS注射后3 h組腹腔巨噬細(xì)胞TLR4,MHC-II,CD80,CD86及CD40的表達(dá)及LPS注射后12 h脾臟NK細(xì)胞胞內(nèi)細(xì)胞因子IFN-γ水平;雞紅細(xì)胞吞噬實(shí)驗(yàn)檢測兩種小鼠正常對照組腹腔巨噬細(xì)胞吞噬功能;并提取兩種小鼠正常對照組腹腔巨噬細(xì)胞體外LPS刺激培養(yǎng),測定上清中TNF-α, IL-6, IL-10, IL-17及IFN-γ的水平。 結(jié)果LPS注射后1 h,SCID小鼠腹腔灌洗液TNF-α水平高于BALB/c小鼠,注射后3 h,IL-10水平明顯低于BALB/c小鼠;正常對照組及LPS注射后3 h,6 h和12 h組,SCID小鼠腹腔巨噬細(xì)胞TNF-αmRNA表達(dá)高于BALB/c小鼠;正常對照組及LPS注射后各時間點(diǎn),SCID小鼠腹腔巨噬細(xì)胞IL-10 mRNA表達(dá)均低于BALB/c小鼠。BALB/c小鼠腹腔巨噬細(xì)胞吞噬百分率及吞噬指數(shù)均高于SCID小鼠腹腔巨噬細(xì)胞;LPS注射后,BALB/c小鼠腹腔巨噬細(xì)胞TLR4, MHC-II, CD80, CD86表達(dá)均明顯升高,SCID小鼠腹腔巨噬細(xì)胞TLR4, MHC-II, CD86表達(dá)無明顯變化,BALB/c小鼠腹腔巨噬細(xì)胞CD40及SCID小鼠腹腔巨噬細(xì)胞CD80,CD40均明顯下降;SCID小鼠NK細(xì)胞胞內(nèi)IFN-γ平均熒光值高于BALB/c小鼠NK細(xì)胞。體外實(shí)驗(yàn)LPS刺激20h后,SCID小鼠腹腔巨噬細(xì)胞較BALB/c小鼠腹腔巨噬細(xì)胞分泌更多的TNF-α,IL-6,但I(xiàn)L-10的分泌明顯偏少。 結(jié)論與野生型BALB/c小鼠比較,SCID小鼠腹腔巨噬細(xì)胞共刺激分子CD80、CD86的表達(dá)自發(fā)性增高,吞噬功能明顯下降。經(jīng)LPS刺激后,腹腔巨噬細(xì)胞TLR4和MHC-II和CD80、CD86分子表達(dá)無增高,但分泌的炎性細(xì)胞因子顯著增加,且NK細(xì)胞胞內(nèi)IFN-γ水平增高。以上表現(xiàn)是SCID小鼠內(nèi)毒素血癥炎癥反應(yīng)失控的主要特點(diǎn)。 第三部分MKP-1在淋巴細(xì)胞對巨噬細(xì)胞活化調(diào)控中的作用 目的在LPS誘導(dǎo)的BALB/c小鼠和SCID小鼠內(nèi)毒素血癥模型基礎(chǔ)上,篩選出可能參與淋巴細(xì)胞對巨噬細(xì)胞活化調(diào)控的信號分子。于體外建立單獨(dú)腹腔巨噬細(xì)胞組及腹腔巨噬細(xì)胞+pan-T細(xì)胞混合培養(yǎng)組模型,采用LPS刺激后,明確所篩選出分子的表達(dá)及作用。 方法將40只雄性BALB/c小鼠和40只雄性SCID小鼠各自隨機(jī)分為正常對照組,LPS注射后1 h,3 h,6 h和12 h組。提取腹腔巨噬細(xì)胞;采用實(shí)時熒光定量PCR檢測腹腔巨噬細(xì)胞SOCS1, SOCS3及MKP-1的mRNA表達(dá),免疫熒光檢測腹腔巨噬細(xì)胞MKP-1蛋白表達(dá)。提取BALB/c小鼠腹腔巨噬細(xì)胞及脾臟pan-T細(xì)胞建立單獨(dú)腹腔巨噬細(xì)胞組及腹腔巨噬細(xì)胞+pan-T細(xì)胞混合培養(yǎng)組模型;LPS刺激后,提取貼壁腹腔巨噬細(xì)胞及細(xì)胞培養(yǎng)上清;實(shí)時熒光定量PCR檢測MKP-1 mRNA的表達(dá);Western Blot檢測腹腔巨噬細(xì)胞MKP-1蛋白表達(dá)水平;用ELISA檢測上清中TNF-α、IL-6及IL-10的水平。 結(jié)果在LPS注射后3 h及6 h,SCID小鼠腹腔巨噬細(xì)胞SOCS1 mRNA表達(dá)明顯高于BALB/c小鼠;在LPS注射后1 h及12 h,BALB/c小鼠SOCS3表達(dá)明顯高于SCID小鼠。正常對照組及LPS注射后, BALB/c小鼠腹腔巨噬細(xì)胞MKP-1 mRNA的表達(dá)均高于SCID小鼠腹腔巨噬細(xì)胞。體外實(shí)驗(yàn),LPS刺激后,腹腔巨噬細(xì)胞與pan-T細(xì)胞共培養(yǎng)細(xì)胞中腹腔巨噬細(xì)胞MKP-1 mRNA及蛋白表達(dá)高于單獨(dú)培養(yǎng)腹腔巨噬細(xì)胞;上清中TNF-α、IL-6水平明顯低于單獨(dú)培養(yǎng)巨噬細(xì)胞,IL-10水平無顯著差異。 結(jié)論內(nèi)毒素血癥小鼠淋巴細(xì)胞并非通過SOCS1和SOCS3信號分子調(diào)控巨噬細(xì)胞活化。Pan-T細(xì)胞可抑制LPS刺激下巨噬細(xì)胞炎性細(xì)胞因子釋放。在LPS誘導(dǎo)炎癥反應(yīng)小鼠模型中淋巴細(xì)胞可能通過促進(jìn)巨噬細(xì)胞MKP-1表達(dá),抑制其炎性細(xì)胞因子的產(chǎn)生。
[Abstract]:Background and objective sepsis is a common complication of severe infection, trauma, burns, and major surgical operations. Further development can lead to septic shock and multiple organ dysfunction syndrome (MODS), which is one of the most important causes of death in critically ill patients. The total number of cases of sepsis in the world is about 18 million / year, and the number of patients in the United States is 75. Ten million / a year, Europe is 135 thousand / a year. The number of deaths in the world is more than 14 thousand / day, and the United States is the main cause of non cardiac ICU death in the United States. The current understanding and treatment of sepsis have improved, but the mortality of sepsis remains high and has become a prominent problem facing modern critical medicine. The root cause is the pus. The basic pathogenesis and mechanism of toxosis have not been fully elucidated. Therefore, early effective prevention and treatment measures are lacking.
The uncontrolled systemic inflammatory response is one of the important reasons for the poor prognosis of sepsis. The innate immune cells are important participants in the inflammatory response, and their abnormal activation can lead to the occurrence of uncontrolled inflammatory reactions. Infection related hemophagocytic syndrome (IAHS) and severe acute respiratory syndrome (SARS), severe H1N1, and so on. The pathological and pathophysiological characteristics of dyed diseases are also out of control systemic inflammatory response syndrome. The abnormal activation of innate immune cells in the above diseases is one of the important causes of the disease. But it is necessary to further study the causes of the abnormal activation of the innate immune cells. The complexity of the interaction of the immune cells in the inflammatory response. Our previous study showed that after the infection of the respiratory syncytial virus (RSV) in the T cell deficiency nude mice, the inflammatory response was heavier than the wild type mice, suggesting that the T cells may inhibit the.Kim in the inflammatory response. Therefore, we speculate that the occurrence of sepsis, IAHS and SARS may be related to the abnormal activation of innate immune cells in the body of lymphocytes in different degrees in the body. The study of the activation and function of the innate immune cells in the lymphocytic sepsis may be the link and effect of the disease. The mechanism research provides a new way of thinking.
Endotoxin plays an important role in the pathogenesis of sepsis caused by gram-negative bacterial infection. Even when the bacterial blood culture is negative, endotoxemia is also present, suggesting that endotoxemia is a separate pathogenic factor of sepsis. Endotoxin has a very extensive and complex biological effect. It is out of control in the pathological process of sepsis. Inflammatory reaction, immune dysfunction, high metabolic state and multiple organ dysfunction can be triggered directly or indirectly by endotoxin. The pathological immune response (inflammatory reaction) of the gram negative bacterial infection model of the severe combined immunodeficiency (SCID) mice depends on the continuous propagation of bacteria and the immune response of the host. This model is difficult to study the single immune response. In order to avoid this kind of situation, we intend to use LPS to induce T, B cell deficiency and severe combined immunodeficiency mice endotoxemia. By observing the biological characteristics of macrophages in SCID mice, the effects of lymphocyte defects on the inflammatory response are revealed. It also provides a new direction and theoretical basis for the prevention and treatment of sepsis.
Objective on the basis of LPS induced BALB/c mice and SCID mice endotoxemia model, the difference of inflammatory response in two mice was compared and the effects of lymphocyte defects on the inherent immune response and inflammatory response were observed.
Methods the general condition and survival rate of LPS mice were observed by intraperitoneal injection of BALB/c and SCID mice. 32 male BALB/c mice and 32 male SCID mice were randomly divided into normal control group, 3 h, 6 h and 12 h groups after LPS injection. The serum, liver and lung tissues of the mice were taken. The serum cereal rotation of two mice was detected by automatic biochemical analyzer. The levels of ammonia enzyme (ALT), glutamic grass transaminase (AST) and blood urea nitrogen (BUN) were measured by H.E staining and double blind method was used to evaluate the pathological damage of the liver and lung. The level of TNF- alpha, IFN- gamma, IL-10, IL-6 and MCP-1 in two kinds of mice was detected by flow cytometry microsphere array (CBA), and the level of serum IL-12, the level and liver of the two kinds of mice were detected by ELISA. Weave the level of TNF- alpha and IL-10 in the homogenate.
Results after LPS induced endotoxemia, SCID mice died at 12~24 H (8/8), and only 1 of BALB/c mice died (1/8); LPS injected 12 h, SCID mice serum ALT, AST were higher than that of BALB/c mice, two mice had no significant difference. The level of -10, IL-6, MCP-1 and IL-4 increased significantly, and the level of cytokines above SCID mice was significantly higher than that of BALB/c mice, and the level of TNF- a in the liver homogenate of SCID mice was higher than that of BALB/c mice after LPS injection, and the level of 6 h was higher than that of the mice after the injection.
Conclusion after LPS induced endotoxemia in mice, compared with the wild type BALB/c mice, SCID mice secreted excessive inflammatory and anti-inflammatory cytokines, resulting in uncontrolled inflammatory reaction and serious organ damage, which was an important cause of death in SCID mice. And the important cause of severe systemic inflammatory response syndrome.
The second part is the comparison of activation and function of lipopolysaccharide induced peritoneal macrophages in BALB/c mice and SCID mice with endotoxemia.
Objective to compare the activation and function of peritoneal macrophages in BALB/c mice and SCID mice on the basis of LPS induced endotoxemia model in BALB/c mice and SCID mice, and to observe the effect of lymphocyte defects on the activation and function of macrophages.
Methods 40 male BALB/c mice and 40 male SCID mice were randomly divided into normal control group, 1 h, 3 h, 6 h and 12 h groups after LPS injection. The peritoneal lavage fluid, peritoneal macrophage and spleen NK cells of mice were taken, and TNF- alpha and IL-10 of peritoneal lavage liquid were detected by ELISA; real-time fluorescent quantitative PCR was used to detect peritoneal macrophages. Expression of alpha and IL-10 mRNA; flow cytometry was used to detect the expression of TLR4, MHC-II, CD80, CD86 and CD40 of peritoneal macrophages in 3 h groups of BALB/c mice and SCID mice after LPS injection and the level of intracellular cytokines in the 12 spleen cells after LPS injection; and two mice of normal control group of peritoneal macrophages were tested by phagocytosis. Phagocytosis; two normal mice were extracted from the normal control group and cultured in vitro stimulated by LPS. The levels of TNF-, IL-6, IL-10, IL-17 and IFN- gamma in the supernatant were measured.
Results the level of TNF- alpha in peritoneal lavage fluid of SCID mice was higher than that of BALB/c mice after 1 h injection, and the level of IL-10 in SCID mice was significantly lower than that of BALB/c mice after injection, and the level of IL-10 was significantly lower than that of BALB/c mice after injection. The normal control group and 3 h, 6 h and 12 h groups after LPS injection were higher than those of the mice; the normal control group and the time points after the injection were in the abdominal cavity. The expression of IL-10 mRNA in macrophages was lower than that of BALB/c mouse.BALB/c mice. The phagocytic percentage and phagocytic index of peritoneal macrophages in.BALB/c mice were higher than that of peritoneal macrophages in SCID mice. TLR4, MHC-II, CD80, CD86 expression of peritoneal macrophages in BALB/c mice were significantly increased after LPS injection, and there was no obvious expression in the peritoneal macrophages in SCID mice. BALB/c mice peritoneal macrophages CD40 and SCID mice peritoneal macrophages CD80, CD40 significantly decreased, SCID mice NK cell IFN- gamma average fluorescence value is higher than the BALB/c mouse NK cells. There is less obvious secretion.
Conclusion compared with the wild type BALB/c mice, the co stimulatory molecule CD80 of peritoneal macrophages of SCID mice increased spontaneously and the phagocytic function decreased obviously. After LPS stimulation, the expression of TLR4 and MHC-II and CD80 in peritoneal macrophages was not increased, but the secreted inflammatory cell factor increased significantly, and the IFN- gamma level in the cell cell of NK cells increased. The above features are the main features of the inflammatory reaction of SCID mice with endotoxemia.
The third part is the role of MKP-1 in regulating lymphocyte activation.
Objective on the basis of the endotoxemia model of LPS induced BALB/c mice and SCID mice, the signal molecules that may participate in the regulation of macrophage activation were screened. The model of a mixed culture group of single peritoneal macrophage and peritoneal macrophage +pan-T cells was established in vitro. After LPS stimulation, the molecular table was clearly screened. Reach and function.
Methods 40 male BALB/c mice and 40 male SCID mice were randomly divided into normal control group. After LPS injection, 1 h, 3 h, 6 h and 12 h were used to extract peritoneal macrophages. The expression of SOCS1, SOCS3 and MKP-1 mRNA in peritoneal macrophages was detected by real-time fluorescent quantitative PCR, and the expression of peritoneal macrophage was detected by immunofluorescence. C mice peritoneal macrophages and spleen pan-T cells were established by the mixed culture group of peritoneal macrophages and +pan-T cells in peritoneal macrophages. After LPS stimulation, the peritoneal macrophages and cell culture supernatants were extracted. The expression of MKP-1 mRNA was detected by real-time fluorescent quantitative PCR; Western Blot was used to detect the expression of MKP-1 protein in peritoneal macrophages. Levels of TNF-, IL-6 and IL-10 in supernatant were detected by ELISA.
Results after LPS injection of 3 h and 6 h, the expression of SOCS1 mRNA in peritoneal macrophages of SCID mice was significantly higher than that of BALB/c mice; 1 h and 12 h after LPS injection, BALB/c mice SOCS3 expression was significantly higher than that of the mice. After LPS stimulation, the expression of MKP-1 mRNA and protein in peritoneal macrophages co cultured cells of peritoneal macrophages and pan-T cells was higher than that of peritoneal macrophages alone. The level of TNF- alpha and IL-6 in the supernatant was significantly lower than that of macrophages alone, and there was no significant difference in the level of IL-10.
Conclusion the lymphocyte of mice with endotoxemia is not mediated by SOCS1 and SOCS3 signaling molecules to regulate macrophage activation of.Pan-T cells to inhibit the release of inflammatory cytokines in macrophages under LPS stimulation. In the mouse model induced by LPS, the lymphocyte may inhibit the production of inflammatory cytokines by promoting the expression of MKP-1 in macrophages.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2011
【分類號】：R392

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