本文關(guān)鍵詞： 膿毒癥 氧醚復合 CLP LPS 炎性因子 Nrf2 HO-1 NF-κB mi RNA　出處：《第四軍醫(yī)大學》2015年碩士論文　論文類型：學位論文

【摘要】：膿毒癥(sepsis)是外科重癥監(jiān)護病房(Intensive Care Unit,ICU)病人死亡的主要原因之一,由于高患病率、高死亡率、高治療費用的特點,使其成為人類健康的巨大威脅。因此,尋找針對膿毒癥的有效救治策略迫在眉睫!前期我們在離體和在體模型上均證實,0.5MAC(minimum alveolar concentration,最低肺泡有效濃度)異氟醚復合60%氧對膿毒癥具有保護效應,抑制膿毒癥后的異常炎癥反應,抑制脂多糖刺激后NF-κB(Nuclear factor Kappa B,核因子-κB)核轉(zhuǎn)位,逆轉(zhuǎn)膿毒癥后部分micro RNA(mi RNA,微小RNA)的上調(diào)。本研究擬在此基礎上,研究一氧化氮(nitric oxide,NO)在氧醚復合治療膿毒癥效應機制中的作用,驗證mi RNA是否參與氧醚復合治療膿毒癥效應機制,研究氧醚復合治療膿毒癥效應中對NF-κB信號通路的具體調(diào)控方式,研究Nrf2/HO-1(核因子相關(guān)因子-2/血紅素氧合酶1)抗炎通路在氧醚復合治療膿毒癥效應機制中的作用,并探討氧醚復合對盲腸結(jié)扎穿刺(cecal ligation and puncture,CLP)所致老齡鼠膿毒癥模型是否也有治療效應。相信本研究的實施將為氧醚復合治療膿毒癥提供更多的實驗依據(jù),也為研發(fā)新的膿毒癥治療策略提供新的可能靶點。研究目的探討0.5MAC異氟醚復合60%氧對膿毒癥治療效應機制,并在老齡鼠上驗證0.5MAC異氟醚復合60%氧及0.5MAC七氟醚復合60%氧對膿毒癥的治療效應。材料與方法實驗1.將243只雄性昆明小鼠(25-30g)隨機分為7組:Sham+NS+Air組、CLP+NS+Air組、CLP+NS+100%Oxy組、CLP+NS+0.5MAC ISO+60%Oxy組、CLP+L-NAME+100%Oxy組、CLP+L-NAME+0.5MAC ISO+60%Oxy組和CLP+L-NAME+Air組。CLP+NS+Air、CLP+NS+100%Oxy、CLP+NS+0.5MAC ISO+60%Oxy、CLP+L-NAME+100%Oxy、CLP+L-NAME+0.5MAC ISO+60%Oxy和CLP+L-NAME+Air組動物使用盲腸結(jié)扎穿刺(CLP)法建立膿毒癥模型,Sham+NS+Air組動物只開腹,不實施盲腸結(jié)扎穿刺。治療組動物在CLP或Sham術(shù)后1h、6h分別給予0.5MAC異氟醚復合60%氧或單純100%氧吸入1h;非治療組直接吸入空氣。CLP或Sham前4h,給所有動物腹腔注射20mg/kg L-NAME或等容積的生理鹽水。觀察動物7天存活情況。檢測指標:血清炎癥因子水平;動脈血氣分析;腹腔灌洗液細菌計數(shù)。實驗2.在我們以往研究中,0.5MAC異氟醚復合60%氧干預可顯著下調(diào)CLP后表達升高的4種mi RNAs,即mi R-133a-3p、mi R-141-3p、mi R-3074-2-3p、mi R-542-3p。本研究中,首先構(gòu)建攜帶目的基因(mi R-133a-3p、mi R-141-3p、mi R-3074-2-3p、mi R-542-3p)的慢病毒載體,然后用慢病毒感染RAW264.7細胞或小鼠外周血白細胞,使之分別高表達這些mi RNA。治療組細胞給予0.5MAC異氟醚復合60%氧治療;非治療組細胞正常培養(yǎng)。干預完成后收集細胞培養(yǎng)上清液檢測炎癥因子水平。實驗3.培養(yǎng)小鼠巨噬細胞(RAW264.7),隨機分為6組:Veh組、Veh+0.5ISO+60%O組、Veh+100%O組、LPS組、LPS+0.5ISO+60%O組和LPS+100%O組。LPS組使用脂多糖刺激細胞建立離體膿毒癥模型;Veh組給予正常培養(yǎng)基。治療組細胞在LPS刺激開始0.5小時后即開始給予0.5MAC異氟醚復合60%氧或單純100%氧治療;非治療組細胞正常培養(yǎng)。LPS刺激2小時后刮取細胞,提取總蛋白,利用Western blot法檢測p-IKKα/β、p-IκBα、p-p65蛋白表達。實驗4.培養(yǎng)RAW264.7細胞,分組及處理同3。LPS刺激2小時后收集細胞培養(yǎng)上清液檢測炎癥因子改變;收集細胞沉淀物,利用細胞免疫熒光法檢測Nrf2核定位情況,利用實時定量PCR和Western blot法檢測細胞Nrf2、HO-1 m RNA或蛋白的表達情況。實驗5.將228只雄性老齡SD大鼠(12-14月齡)及120只青年SD大鼠(2-3月齡)隨機分為6組:Sham+Air組、Sham+0.5MAC ISO+60%Oxy組、Sham+0.5MAC SEV+60%Oxy組、CLP+Air組、CLP+0.5MACISO+60%Oxy組和CLP+0.5MAC SEV+60%Oxy組。CLP組動物采用盲腸結(jié)扎穿刺法建立膿毒癥模型,Sham組不進行盲腸結(jié)扎穿刺術(shù)。治療組動物于CLP或Sham術(shù)后1h、6h分別給予0.5MAC異氟醚復合60%氧氣吸入1h,或在CLP或Sham術(shù)后6h給予動物0.5MAC七氟醚復合60%氧氣吸入2h。非治療組動物直接吸入空氣,作為對照。觀察動物7天存活情況。于老齡鼠CLP術(shù)后24h取材,包括取一側(cè)肺,做HE染色后觀察病理損傷情況;取另一側(cè)肺,計算肺濕干比,評價肺水腫程度;進行肺泡灌洗,收集灌洗液后檢測蛋白漏出;從右心室取血,離心后收集血清檢測炎癥因子、生化指標等;收集腹腔灌洗液,離心后收集上清,檢測炎癥因子;于股動脈處取血,立即送檢進行血氣分析。結(jié)果實驗1.100%氧及0.5MAC異氟醚復合60%氧可顯著提高膿毒癥小鼠存活率,抑制CLP所致異常的炎癥反應,改善氧合情況,并增強細菌清除能力。給予NO合成酶抑制劑后,上述治療效應均被逆轉(zhuǎn)。這些結(jié)果表明,NO參與了100%氧和0.5MAC異氟醚復合60%氧治療膿毒癥效應機制。實驗2.用慢病毒感染RAW264.7細胞,高表達mi R-133a-3p、mi R-3074-2-3p、mi R-542-3p后,0.5MAC異氟醚復合60%氧抑制LPS所致異常炎性反應的效應被部分逆轉(zhuǎn)。其次,用慢病毒感染CLP小鼠外周血白細胞,高表達mi R-133a-3p、mi R-3074-2-3p、mi R-542-3p后,0.5MAC異氟醚復合對CLP所致異常炎性反應的抑制效應也被部分逆轉(zhuǎn)。這些結(jié)果提示,mi RNAs參與氧醚復合治療膿毒癥效應機制。實驗3.LPS刺激可誘導細胞內(nèi)p-IKKα/β、p-IκBα、p-p65蛋白表達水平增高,給予100%氧和0.5MAC異氟醚復合60%氧干預后,細胞p-IKKα/β、p-IκBα、p-p65蛋白表達水平明顯下調(diào)。這些結(jié)果提示,100%氧和0.5MAC異氟醚復合60%氧是通過抑制IKKα/β、IκBα、p65蛋白磷酸化,從而抑制NF-κB激活,發(fā)揮其抗炎效應。實驗4.LPS刺激RAW264.7細胞2h后,細胞培養(yǎng)上清液中炎性因子水平明顯增高,細胞Nrf2及其靶基因HO-1的m RNA和蛋白表達水平降低。給予100%氧或0.5MAC異氟醚復合60%氧干預后,可抑制LPS刺激后炎性因子水平的增高,細胞Nrf2及HO-1的m RNA表達水平升高,細胞漿中Nrf2蛋白表達有降低趨勢,而細胞核中Nrf2蛋白表達增高,入核明顯增多;細胞總蛋白中HO-1的蛋白表達升高。這些結(jié)果表明,100%氧和0.5MAC異氟醚復合60%氧干預治療離體膿毒癥效應與Nrf2/HO-1抗炎通路密切相關(guān)。實驗5.對于老齡SD大鼠及青年SD大鼠,CLP組后7天生存率均明顯低于Sham組,而給予0.5MAC異氟醚或七氟醚復合60%氧干預后,動物7天存活率均顯著提高。在老齡SD大鼠CLP后24h進行取材并發(fā)現(xiàn),CLP組老齡鼠的肺組織出現(xiàn)明顯病理性損傷,血清及腹腔灌洗液中炎癥因子和生化指標水平均明顯高于Sham組;給予0.5MAC異氟醚或七氟醚復合60%氧干預均可顯著改善肺損傷,并減輕CLP后炎癥因子、生化指標、動脈血氣等各項指標的異常改變。這些結(jié)果說明,氧醚復合對老齡鼠膿毒癥模型具有治療效應。結(jié)論我們的研究結(jié)果表明:NO參與了氧醚復合治療膿毒癥效應機制;mi RNAs參與氧醚復合治療膿毒癥效應機制;氧醚復合是通過抑制IKKα/β、IκBα、p65蛋白磷酸化,抑制NF-κB激活,從而發(fā)揮其抗炎效應的;氧醚復合對離體膿毒癥的治療效應與Nrf2/HO-1通路關(guān)系密切;氧醚復合對老齡鼠膿毒癥模型具有治療效應。
[Abstract]:Sepsis (sepsis) is a surgical ICU (Intensive Care Unit, ICU) is one of the main causes of death of patients, due to the high prevalence rate, high mortality, high treatment costs, make it become a huge threat to human health. Therefore, in order to find the effective treatment of sepsis early we strategy imminent! In vitro and in vivo models have confirmed that 0.5MAC (minimum alveolar concentration, the minimum alveolar concentration of isoflurane and 60% oxygen) has a protective effect on sepsis, inhibit the abnormal inflammatory response after sepsis, inhibition of lipid polysaccharide stimulated NF- kappa B (Nuclear factor Kappa B, nuclear factor kappa B part RNA) nuclear translocation, micro reversed after sepsis (MI RNA, micro RNA) increase. This study based on the research of nitric oxide (nitric oxide, NO) in the treatment of sepsis oxygen ether compound effect mechanism plays a role in the verification of MI RNA is involved in Oxygen ether compound in the treatment of sepsis effect mechanism, the specific regulation of NF- B pathway of oxygen ether complex in the treatment of sepsis effect, Nrf2/HO-1 (nuclear factor related factor -2/ heme oxygenase 1) the effect of anti-inflammatory pathway in the treatment of sepsis oxygen ether compound effect mechanism, and explore the puncture oxygen ether complex (cecal ligation and of cecal ligation and puncture, CLP) is caused by the aging rat model of sepsis also have therapeutic effect. I believe that the implementation of this study will provide more experimental basis for oxygen ether compound in the treatment of sepsis, may also provide a new target for the development of a new strategy for the treatment of sepsis. Objective to research 0.5MAC isoflurane 60% oxygen for the treatment of sepsis effect mechanism, and verify the therapeutic effect of 0.5MAC isoflurane 60% oxygen and 0.5MAC sevoflurane 60% oxygen for sepsis in aged rats. The experimental materials and methods 1. 243 Male Kunming mice (25-30g) were randomly divided into 7 groups: Sham+NS+Air group, CLP+NS+Air group, CLP+NS+100%Oxy group, CLP+NS+0.5MAC ISO+60%Oxy group, CLP+L-NAME+100%Oxy group, CLP+L-NAME+0.5MAC group and ISO+60%Oxy group CLP+L-NAME+Air.CLP+NS+Air, CLP+NS+100%Oxy CLP+NS+0.5MAC, ISO +60%Oxy, CLP+L-NAME+100%Oxy CLP+L-NAME+0.5MAC, ISO+60%Oxy and CLP+L-NAME+Air group animal using cecal ligation and puncture (CLP) method to establish the model of sepsis. Sham+NS+Air group of animal only open, not the implementation of cecal ligation and puncture. The treatment group in the animal CLP or after Sham 1H and 6h 0.5MAC were given isoflurane 60% oxygen or pure oxygen inhalation 100% 1H non treatment group; direct inhalation of air.CLP or Sham before 4h, saline to all animal intraperitoneal injection of 20mg/kg L-NAME or equal volume 7 days. To observe animal survival. Measure the levels of serum inflammatory factor analysis; arterial blood gas; peritoneal lavage fluid Bacteria count. Experiment 2. in our previous study, 60% 0.5MAC isoflurane oxygen intervention expression of 4 mi RNAs increased significantly after MI R-133a-3p downregulation of CLP, MI, R-141-3p, MI, R-3074-2-3p, MI and R-542-3p. in this study, firstly, carrying the target gene (MI R-133a-3p, MI R-141-3p, MI R-3074-2-3p, MI R-542-3p) the lentiviral vector, and then use the peripheral white blood cells RAW264.7 cells or mice infected with lentivirus, which were high expression of these mi RNA. cells treated with 0.5MAC treatment group isoflurane 60% oxygen therapy; treatment of non normal cultured group cells. After intervention collected cell culture supernatant was detected. The level of inflammatory factors in experiment 3. cultured mouse macrophages (RAW264.7), were randomly divided into 6 groups: Veh group, Veh+0.5ISO+60%O group, Veh+100%O group, LPS group, established in vitro sepsis model in LPS+0.5ISO+60%O group and LPS+100%O group group.LPS cells stimulated by lipopolysaccharide Type; Veh group was given normal medium. The treatment group in LPS stimulated cells began to start giving 0.5MAC isoflurane 60% oxygen or pure oxygen treatment is 100% after 0.5 hours; the non treatment group were cultured for 2 hours after.LPS stimulation and scrape cells, the total protein extracted by Western blot method for detecting p-IKK alpha / beta, p-I kappa B alpha, p-p65 protein expression in cultured RAW264.7 cells. In experiment 4., grouping and treatment with 3.LPS stimulation after 2 hours cell culture supernatant was determined by collecting inflammatory change; collecting cells precipitate, detection of nuclear localization of Nrf2 using cell immunofluorescence, cell Nrf2 detection by real-time quantitative PCR and Western blot method, the expression of HO-1 m RNA or protein. In experiment 5., 228 old male SD rats (12-14 months old) and 120 young SD rats (2-3 months old) were randomly divided into 6 groups: Sham+Air group, Sham+0.5MAC ISO+60%Oxy group, Sham+0.5MAC SEV +60%Oxy group, CLP+Air group, C LP+0.5MACISO+60%Oxy group and CLP+0.5MAC group SEV+60%Oxy group.CLP animal model of sepsis was established by cecal ligation and puncture, cecal ligation and puncture without Sham group. Treatment group animal in CLP or Sham after 1h, 6h were given 0.5MAC 60% 1H isoflurane inhalation of oxygen, or as a control group. In the CLP or Sham after 6h to give the animal 0.5MAC sevoflurane 60% oxygen inhalation 2h. non treatment group animal directly into the air, to observe the animal survival. In 7 days old rats after CLP 24h were taken including lung pathological injury after HE staining; and on the other side of the lung, calculate the lung wet to dry ratio, evaluate the degree of pulmonary edema; alveolar lavage detection of protein leakage, collected lavage fluid; blood from the right ventricle, inflammatory factors in serum collected after centrifugation, biochemical indicator; collect peritoneal lavage fluid, after centrifugation the supernatant was collected for detection of inflammation in femoral artery; Blood inspection immediately for blood gas analysis. The results of experiment 1.100% and 60% oxygen oxygen 0.5MAC isoflurane can significantly improve the survival rate of mice with sepsis, inhibiting the inflammatory reaction caused by abnormal CLP, improve oxygenation, and enhance bacterial clearance ability. NO synthase inhibitor, the treatment effects were reversed. These results indicate that in 100%, NO 0.5MAC 60% isoflurane combined oxygen and oxygen in the treatment of sepsis effect. Experiment 2. using lentiviral infection of RAW264.7 cells with high expression of MI, R-133a-3p, MI, R-3074-2-3p, MI, R-542-3p, 0.5MAC effect of isoflurane 60% oxygen inhibits LPS induced abnormal inflammatory response was partially reversed. Secondly, with slow virus infection CLP mice peripheral white blood cells, the high expression of MI R-133a-3p, MI R-3074-2-3p, MI R-542-3p, the inhibitory effect of 0.5MAC isoflurane on CLP induced abnormal inflammatory response was also partially reversed these results. That MI RNAs is involved in oxygen ether complex in the treatment of sepsis. The effect mechanism of 3.LPS stimulation can induce intracellular p-IKK alpha / Beta Kappa B alpha, p-I, p-p65 protein expression level increased, giving 100% oxygen and 60% 0.5MAC isoflurane oxygen intervention, cell p-IKK alpha / beta, p-I kappa B alpha, p-p65 expression protein was down regulated. These results suggest that 100% 0.5MAC oxygen and isoflurane 60% oxygen through inhibition of IKK alpha / beta, I kappa B alpha, p65 protein phosphorylation, thereby inhibiting NF- kappa B activation, exert its anti-inflammatory effect. Experimental 4.LPS stimulation of RAW264.7 cells after 2H cell culture supernatant in inflammatory factor level obviously increased expression of M RNA and protein in Nrf2 cells and its target gene HO-1 decrease. Given 100% oxygen or 0.5MAC isoflurane 60% oxygen intervention can increase the level of inflammatory factors in the inhibition of LPS stimulation, increased the expression level of M Nrf2 and HO-1 RNA cells, the expression of Nrf2 protein in the cytoplasm Decreased, and the expression of Nrf2 protein in the nucleus increased into the nucleus increased significantly; the expression of HO-1 protein in total cell protein increased. These results indicated that 100% 0.5MAC oxygen and isoflurane 60% oxygen treatment in vitro sepsis effect and Nrf2/HO-1 anti-inflammatory pathway are closely related. In experiment 5. aged SD rats and young SD in group CLP, after the 7 day survival rate was significantly lower than that of group Sham, and given 0.5MAC of isoflurane or sevoflurane combined with 60% oxygen intervention, 7 animal survival rate was significantly improved. In aged SD rats after CLP 24h were collected and found that the CLP group in aged rat lung tissues appeared obvious pathological injury, serum and peritoneal lavage fluid in inflammatory cytokines and biochemical indexes were obviously higher than Sham group; 0.5MAC isoflurane or sevoflurane combined 60% oxygen intervention can significantly improve lung injury, and reduce inflammatory factors after CLP, arterial blood gas and other biochemical indicators. The abnormal changes of indexes. These results indicated that oxygen ether composite on the aging rat model of sepsis has a therapeutic effect. Conclusion our results suggest that NO is involved in the oxygen ether compound in the treatment of sepsis effect mechanism; MI RNAs in oxygen ether complex in the treatment of sepsis effect mechanism; oxygen ether composite by inhibiting IKK alpha / beta, I kappa B alpha, p65 phosphorylation and inhibition of NF- K B activation, so as to exert its anti-inflammatory effect; oxygen ether complex on the treatment effect and Nrf2/HO-1 pathway in vitro sepsis closely; oxygen ether compound on aged rat model of sepsis has a therapeutic effect.

【學位授予單位】：第四軍醫(yī)大學
【學位級別】：碩士
【學位授予年份】：2015
【分類號】：R614

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10 劉旭;張_g;;膿毒癥心功能變化及其監(jiān)測的研究進展[A];2010全國中西醫(yī)結(jié)合危重病、急救醫(yī)學學術(shù)會議論文匯編[C];2010年

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