乙酸对脓毒症小鼠巨噬细胞糖代谢的影响及其可能机制研究

发布时间：2018-05-12 23:10

本文选题：乙酸 + 脓毒症　；参考：《第二军医大学》2017年博士论文

【摘要】：研究背景与目的:脓毒症是指由感染引起的全身炎症反应综合征,伴有脏器功能障碍,但其确切分子机制还不清楚,缺乏有效的治疗方法。巨噬细胞作为脓毒症促炎因子的主要来源,其代谢过程发挥着重要作用。巨噬细胞的糖酵解作为治疗靶点越来越受到人们的重视。本文研究了在小鼠盲肠结扎穿孔致脓毒症模型中,糖代谢重要中间产物之一乙酸对小鼠的保护作用及其作用机制。研究方法:1.在体观察乙酸对脓毒症小鼠的保护作用:采用小鼠盲肠结扎穿孔(CLP)脓毒症模型,观察在CLP术后30分钟分别腹腔注射乙酸250mg/kg或500mg/kg对小鼠7天生存率、CLP术后12小时肝和肺组织损伤、腹腔细菌清除率和小鼠血清促炎因子的水平。采用腹腔注射LPS建立小鼠内毒素血症模型,分别在建模前12天连续给予水中添加乙酸(150mmol/l)或建模前30分钟后给予乙酸腹腔注射(500mg/kg)预处理,检测小鼠血清促炎因子的水平。2.离体观察乙酸对巨噬细胞的作用:体外分离培养小鼠骨髓来源的巨噬细胞(BMDM)、小鼠腹腔巨噬细胞、人外周血单核细胞(PBMC)、人类THP-1细胞和人CD14+细胞,分别用乙酸(5~100mmol/l)预处理0.5h、1h、2h后用LPS刺激,6h后检测小鼠血清促炎因子TNF-α和IL-6的水平。3.乙酸抑炎的机制探讨:首先,通过离体细胞进一步探讨乙酸对巨噬细胞免疫功能影响的机制。体外分离培养BMDM,将BMDM和RAW 264.7巨噬细胞系用乙酸(10mmol/l)预处理0.5h,在LPS(100ng/ml)刺激后15min、30min和60min收集细胞,采用Western Blotting法测定NF-κB p65、JNK、ERK和p38 MAPK磷酸化的改变。并用si RNA敲减GPR41、GPR43两个乙酸受体,检测小鼠血清促炎因子TNF-α和IL-6的水平。其次观察乙酸对糖酵解的影响。体外分离培养BMDM,用乙酸10mmol/l预处理后0.5h LPS刺激,LPS刺激后6h收集细胞与上清,测定BMDMs培养上清中乳酸浓度,分析2-NBDG摄取,检测细胞中糖酵解关键酶GLUT1,PFKFB3,HK2,MCT4m RNA的表达以及细胞酸化率(ECAR)和氧耗率(OCR)。随后通过γ-干扰素(IFN-γ)或粒细胞-巨噬细胞集落刺激因子(GM-CSF)预处理增强BMDM糖酵解后进一步观察乙酸对巨噬细胞糖代谢及促炎因子的影响。体外分离培养BMDM,用100ng/ml的IFN-γ或GM-CSF预孵育3小时,乙酸10mmol/l预处理后,LPS刺激6h,收集细胞和上清,ELISA法测上清TNF-α和IL-6的浓度;比色法测上清乳酸浓度;Q-PCR法测细胞GLUT1、HK2、MCT4、PFKFB3的m RNA表达;流式细胞仪分析细胞表面的GLUT1表达;Western Blotting分析测定NF-κB p65和m TOR磷酸化改变。4.乙酸如何抑制糖酵解:首先离体观察乙酸预处理对HIF-1αm RNA以及蛋白表达的影响。体外分离培养BMDM,用乙酸(10mmol/l)预处理0.5h,在LPS(100ng/ml)刺激后15min和30min,收集细胞,Q-PCR法测细胞的HIF-1αm RNA;Western Blotting法测定HIF-1α蛋白的表达。随后探讨HIF-1α是不是乙酸作用所必需的,我们在体内和体外用DMOG,一种HIF-1α脯氨酰羟化酶的竞争性抑制剂。将BMDM,先用DMSO或DMOG(0.5mmol/l)孵育2.5h,然后乙酸10mmol/l预处理0.5h,再用LPS100μg/ml刺激6h后收集上清,ELISA法测定上清TNF-α和IL-6水平。观察DMOG是否能反转乙酸降低LPS诱导的促炎因子的产生;Gl UT1、HK2、MCT4和PFKFB3的m RNA表达;巨噬细胞表面GLUT1表达;培养基中乳酸和葡萄糖的消耗率以及NF-κB的磷酸化改变。又将RAW264.7细胞,转染HIF-1α特异性载体和空白载体24 h后,观察过表达HIF-1α对乙酸降低LPS诱导的促炎因子的产生作用的影响。最后在体研究HIF-1α是不是乙酸保护脓毒症小鼠作用所必需的:将40只野生型(wild type,WT)C57BL/6小鼠随机分为假手术组(sham,n=8),CLP模型组(CLP,n=8),DMOG+CLP组(DMOG+CLP,n=8),乙酸处理组(CLP+A,n=8)和乙酸+DMOG组(DMOG+CLP+A,n=8)五个组。用DMOG(320mg/kg)腹腔注射2.5h,随后进行CLP术,然后用乙酸(500mg/kg,ip)0.5h,观察小鼠7天生存率;CLP模型后12小时收集小鼠肝肺组织、外周血血清、腹腔灌洗液。HE染色观察各组小鼠肝和肺的病理变化;ELISA法测外周血血清促炎因子TNF-α、IL-6、IL-1β水平等指标。结果:1.在体观察乙酸对脓毒症小鼠的保护作用:CLP组小鼠生存率为37.5%,乙酸处理组(250mg/kg、500mg/kg)的生存率分别为75%和85%,差异有统计学意义(P0.05)。提示乙酸可明显改善CLP小鼠的生存率。CLP明显造成小鼠肝肺组织损伤,可见肝静脉、中央静脉和肝窦扩张淤血,肝小叶肝细胞萎缩和坏死,炎性细胞浸润、变性;肺小静脉和肺泡壁毛细血管扩张,充血和纤维组织增生;肝功能指标AST显著上升;腹膜细菌计数上升;血清TNF-α、IL-6、IL-1β水平升高。与CLP组相比,乙酸处理组的肝肺组织损伤明显减轻,肝静脉、中央静脉和肝窦淤血,肝细胞坏死区域以及炎性细胞浸润显著减少;肺小静脉和肺泡壁毛细血管管壁重建增加,肺毛细血管充血和纤维化增生减少。乙酸处理组的AST明显下降,腹膜细菌计数显著降低;血浆TNF-α、IL-6、IL-1β水平下降(P0.05)。提示乙酸可改善脓毒症造成的组织损伤,减少促炎因子的释放并增强病原体的清除能力。LPS诱导的小鼠内毒素血症模型结果显示,LPS能显著增加小鼠血清的TNF-α和IL-6,口服给药乙酸组或者腹腔注射给予乙酸组血清的TNF-α和IL-6明显下降,说明乙酸对LPS介导的体内促炎因子释放有抑制作用。2.离体观察乙酸对巨噬细胞的作用:在BMDM、小鼠腹腔巨噬细胞、人外周血单个核细胞(PBMC)、人CD14细胞以及人类的THP-1细胞中,LPS组的促炎细胞因子TNF-α和IL-6水平以及m RNA显著增加,乙酸处理组的TNF-α和IL-6水平以及m RNA较LPS组明显降低,提示乙酸对LPS诱导的TNF-α和IL-6释放和m RNA增加有抑制作用,且此抑制作用呈剂量依赖性和时间依赖性。在体外证实了乙酸的抑炎作用。3.乙酸抑炎的机制探讨:在BMDM,LPS组的NF-κB p65的磷酸化显著增加,而乙酸预处理导致激活的NF-k B p65显著减少。LPS组的JNK、ERK和p38 MAPK的磷酸化显著增加,然而,乙酸预处理的JNK、ERK和p38 MAPK的磷酸化与LPS组无显著差异。在BMDM,单独敲减GPR43和GPR41两个乙酸受体,或同时敲减GPR43和GPR41的表达,LPS组的TNF-α和IL-6显著增加,乙酸处理组的TNF-α和IL-6较LPS组明显降低;与乙酸组相比,无论单独敲减GPR43或GPR41的表达,还是同时敲减GPR43和GPR41的表达,TNF-α和IL-6的释放均无显著差异,提示GPR43和GPR41可能不涉及乙酸的抗炎作用。在BMDM,LPS组的血清乳酸水平、2-NBDG摄取略有增加,GLUT1、PFKFB3、HK2、MCT4 m RNA的表达迅速增加,巨噬细胞表面GLUT1表达明显增加;而乙酸处理组的血清乳酸水平、2-NBDG摄取降低,GLUT1、PFKFB3、HK2、MCT4 m RNA的表达显著下降,巨噬细胞表面GLUT1表达也显著降低。这表明,在BMDM中,乙酸抑制LPS诱导的糖酵解率和葡萄糖消耗率增加,提示在LPS刺激后,乙酸抑制糖酵解关键酶的表达。预孵育IFN-γ或GM-CSF增加BMDM的糖酵解后,相较LPS组,乙酸组的TNF-α和IL-6释放减少以及GLUT1,PFKFB3,HK2,MCT4 m RNA的表达降低;而预孵育IFN-γ或GM-CSF的乙酸治疗组,可见乙酸组的TNF-α和IL-6释放减少以及GLUT1、PFKFB3、HK2、MCT4 m RNA的表达降低几乎被完全反转。表明增加糖酵解能逆转乙酸的抗炎作用。在LPS诱导的内毒素血症模型中,乙酸处理组的小鼠脾巨噬细胞的2-NBDG摄取显著减少,说明乙酸在体内抑制LPS导致的葡萄糖摄取升高。4.HIF-1α在糖酵解中的作用:在BMDM,LPS组的HIF-1αm RNA和蛋白表达增加,乙酸组的HIF-1αm RNA和蛋白表达显著降低,差异有统计学意义(P0.05)。表明在乙酸在m RNA水平和蛋白水平抑制LPS刺激引起的HIF-1α上调。用DMOG抑制BMDM的HIF-1α表达,结果显示,LPS组的TNF-α和IL-6显著增加,乙酸处理组的TNF-α和IL-6较LPS组明显降低,DMOG+乙酸组的TNF-α和IL-6与LPS组无显著差别。在RAW264.7细胞,通过转染HIF-1α特异性载体过表达HIF-1α,结果显示,LPS组的TNF-α和IL-6显著增加,乙酸处理组的TNF-α和IL-6较LPS组明显降低,而HIF-1α过表达+乙酸组的TNF-α和IL-6与LPS组无显著差别。说明HIF-1α是乙酸抑制LPS诱导的促炎因子释放所必需的。在BMDM,LPS组的GLUT1、PFKFB3、HK2、MCT4 m RNA表达明显升高,巨噬细胞表面GLUT1表达明显增加,乳酸产生和葡萄糖水平明显增加;乙酸组的GLUT1、PFKFB3、HK2、MCT4 m RNA的表达显著降低;DMOG+乙酸组的GLUT1、PFKFB3、HK2、MCT4 m RNA的表达显著降低,巨噬细胞表面GLUT1表达明显减少,乳酸产生和葡萄糖水平明显减少,与LPS组无显著差异。这表明乙酸降低LPS刺激产生的细胞因子至少部分通过HIF-1α依赖性的糖酵解的调节。在BMDM,LPS组的NF-κB p65磷酸化增加,乙酸组的NF-κB p65磷酸化显著降低;DMOG+乙酸组的NF-κB p65磷酸化增加,与LPS组无显著差异;证明DMOG能完全逆转乙酸抑制激活NF-κB的作用。最后在体研究HIF-1α是不是乙酸保护脓毒症小鼠作用所必需的:用DMOG在体内抑制脓毒症小鼠巨噬细胞的HIF-1α表达,与CLP组相比,乙酸组小鼠的死亡率显著降低,肝肺组织损伤明显减轻,肝静脉、中央静脉和肝窦淤血,肝细胞坏死区域以及炎性细胞浸润显著减少;肺小静脉和肺泡壁毛细血管管壁重建增加,肺毛细血管充血和纤维化增生减少。乙酸处理组的AST明显下降,腹膜细菌计数显著降低;血浆IL-6、IL-1β,TNF-α水平下降;而用DMOG预处理后,乙酸降低死亡率的作用明显反转,乙酸改善脓毒症造成的组织损伤,减少促炎因子的释放并增强病原体的清除能力也明显被反转。说明HIF-1α在乙酸引起的糖酵解改变中起关键作用。结论:乙酸可通过抑制LPS导致的HIF-1α表达来抑制LPS导致的糖酵解,进而减少促炎因子的释放,由此缓解脓毒症导致的脏器功能损害,提高其生存率。
[Abstract]:Background and purpose: sepsis is a systemic inflammatory response syndrome caused by infection, accompanied by organ dysfunction, but its exact molecular mechanism is not clear and effective. Macrophages play an important role in the metabolic process of septic proinflammatory factors. The glycolysis of macrophages is used as a cure. In this paper, the protective effect and mechanism of acetic acid, one of the important intermediate products of sugar metabolism, in mice were studied in the model of cecal ligation and perforation induced sepsis in mice. 1. in vivo observation of the protective effect of acetic acid on sepsis in mice: the use of cecum ligation and perforation (CLP) sepsis in mice The model was to observe the 7 natural survival rate of mice by intraperitoneal injection of acetic acid 250mg/kg or 500mg/kg 30 minutes after CLP, 12 hours of liver and lung tissue injury after CLP, the clearance rate of peritoneal bacteria and the level of serum proinflammatory factors in mice. The mice endotoxemia model was established by intraperitoneal injection of LPS, and the water was added to the water for 12 days before modeling, respectively. Acetic acid (150mmol/l) or intraperitoneal injection of acetic acid (500mg/kg) was given 30 minutes before the modeling to detect the level of serum proinflammatory factors in mice by.2. in vitro. The effect of acetic acid on macrophages was observed in vitro: isolated and cultured macrophages (BMDM), mouse peritoneal macrophages, human peripheral blood mononuclear cells (PBMC), and human THP-1 thin in vitro. The cell and human CD14+ cells were pretreated with acetic acid (5~100mmol/l) for 0.5h, 1H, 2h and LPS stimulation. After 6h, the mechanism of serum proinflammatory factor TNF- alpha and IL-6 level.3. acetic acid inhibition was investigated. First, the mechanism of acetic acid on the immune function of macrophages was further investigated by the isolated cells. In vitro isolation and culture BMDM, BMDM and 2 The 64.7 macrophage system was pretreated with acetic acid (10mmol/l), 0.5h was pretreated with LPS (100ng/ml), 15min, 30min and 60min were collected after the stimulation of LPS (100ng/ml). Western Blotting method was used to determine NF- kappa B p65. The effects of acetic acid on glycolysis were observed. BMDM was isolated and cultured in vitro, 0.5h LPS was pretreated with acetic acid 10mmol/l. After LPS stimulation, 6h collected cell and supernatant, determined the concentration of lactic acid in BMDMs culture supernatant, analyzed 2-NBDG uptake, and detected the expression of the key enzymes, GLUT1, PFKFB3, HK2, MCT4m, and the rate of acidification and oxygen consumption. (OCR). The effect of acetic acid on macrophage glucose metabolism and proinflammatory factors was further observed by preconditioning with interferon gamma (IFN- gamma) or granulocyte macrophage colony stimulating factor (GM-CSF). BMDM was isolated and cultured in vitro, incubated with 100ng/ml IFN- gamma or GM-CSF for 3 hours, and LPS stimulated 6h after acetic acid 10mmol/l preconditioning. To collect cells and supernatants, the concentration of TNF- alpha and IL-6 in the supernatant was measured by ELISA; the concentration of lactic acid in the supernatant was measured by colorimetric method; the m RNA expression of GLUT1, HK2, MCT4, PFKFB3 in cells was measured by Q-PCR; the flow cytometer analyzed the GLUT1 expression of the cell surface; The effects of acetic acid pretreatment on the expression of HIF-1 alpha m RNA and protein were observed. BMDM was isolated and cultured in vitro, 0.5h was pretreated with acetic acid (10mmol/l), 15min and 30min were collected after LPS (100ng/ml) stimulation, and the cells were collected and Q-PCR method was used to determine the expression of alpha protein. In the body and in vitro, we use DMOG in vivo and in vitro, a competitive inhibitor of HIF-1 alpha prolyl hydroxylase. BMDM is incubated with DMSO or DMOG (0.5mmol/l) to incubate 2.5h first, and then acetic 10mmol/l pretreatments 0.5h, then LPS100 um g/ml stimulates 6h to collect the supernatant. The production of pro-inflammatory factors; the expression of M RNA in Gl UT1, HK2, MCT4 and PFKFB3; the expression of GLUT1 on the surface of macrophages; consumption of lactic acid and glucose in the medium and phosphorylation of NF- kappa B. RAW264.7 cells were also transfected to HIF-1 alpha specific carrier and blank carrier 24. The effect of factor production. Finally, in vivo study of whether HIF-1 alpha was necessary for the action of acetic acid to protect sepsis: 40 wild type (WT) C57BL/6 mice were randomly divided into the sham operation group (sham, n=8), CLP model group (CLP, n=8), DMOG+CLP group (DMOG+), acetic acid treatment group and acetic acid group. The five groups were treated with DMOG (320mg/kg) intraperitoneal injection of 2.5h, followed by CLP, and then using acetic acid (500mg/kg, IP) 0.5h to observe the 7 natural survival rate of mice. After CLP model, the liver and lung tissue of mice were collected 12 hours after CLP model, and the pathological changes of liver and lung in each group were observed by.HE staining in the peritoneal lavage solution, and TNF- alpha of peripheral blood serum proinflammatory factor in peripheral blood was measured by ELISA method. IL-1 beta level and other indicators. Results: 1. the protective effect of acetic acid on sepsis in mice was observed in the body of acetic acid: the survival rate of the CLP group was 37.5%, the survival rate of the acetic acid treatment group (250mg/kg, 500mg/kg) was 75% and 85% respectively, the difference was statistically significant (P0.05). It was suggested that the survival rate of the acetic acid can be obviously improved by.CLP in the mice, and the liver and lung tissue damage in mice was obviously caused. The hepatic vein, the central vein and the hepatic sinus dilated and congestion, hepatic lobular liver cell atrophy and necrosis, inflammatory cell infiltration, degeneration, pulmonary venules and alveolar capillary dilatation, hyperemia and fibrous tissue proliferation, liver function index AST increased significantly, peritoneal bacteria count increased; serum TNF- alpha, IL-6, IL-1 beta levels increased. Compared with CLP group, acetic acid The injury of liver and lung tissue in the treatment group was obviously reduced, the hepatic vein, the central vein and the hepatic sinus congestion, the necrosis area of the liver cell and the inflammatory cell infiltration decreased significantly, the reconstruction of the capillary wall of the pulmonary venule and the alveolar wall increased, the pulmonary capillary congestion and the fibrotic hyperplasia decreased. The AST of the acetic acid treatment group was significantly decreased and the count of peritoneal bacteria was significant. Decrease in plasma TNF- alpha, IL-6, IL-1 beta level (P0.05). It suggests that acetic acid can improve tissue damage caused by sepsis, reduce the release of pro-inflammatory factors and enhance the scavenging ability of pathogens,.LPS induced mouse endotoxemia model results show that LPS can significantly increase the TNF- alpha and IL-6 in mice serum, oral Administration of acetic acid group or intraperitoneal injection. TNF- alpha and IL-6 decreased significantly in the serum given to acetic acid, indicating that acetic acid inhibits the release of pro-inflammatory factors mediated by LPS in vivo and the effect of acetic acid on the macrophage is observed in.2. in vitro: in BMDM, mouse peritoneal macrophages, human peripheral blood mononuclear cells (PBMC), human CD14 cells and human THP-1 cells, the proinflammatory cells in group LPS The levels of TNF- alpha and IL-6 and m RNA increased significantly, and the TNF- alpha and IL-6 levels in the acetic acid treatment group and the m RNA were significantly lower than those of the LPS group. It suggested that acetic acid inhibited the TNF- alpha and IL-6 release and increasing of LPS induced IL-6, and the inhibition was dose-dependent and time dependent. The mechanism of inflammation: in BMDM, the phosphorylation of NF- kappa B p65 in group LPS increased significantly, while acetic acid pretreatment led to the activation of NF-k B p65 to significantly reduce the JNK of.LPS group, and the phosphorylation of ERK and p38 significantly increased. However, there was no significant difference between the acetic acid pretreatment and the phosphorylation of the NF-. The TNF- A and IL-6 of the LPS group increased significantly, and the TNF- alpha and IL-6 in the LPS group were significantly lower than those in the LPS group, and there was no significant difference in the expression of GPR43 or GPR41, or at the same time, and the release of GPR43 and GPR41. 1 may not involve the anti-inflammatory effect of acetic acid. In BMDM, the level of serum lactic acid in group LPS, 2-NBDG uptake slightly increased, GLUT1, PFKFB3, HK2, MCT4 m RNA increased rapidly, and the expression of GLUT1 on the surface of macrophages increased significantly, while the serum lactic acid level of the acetic acid treatment group decreased, GLUT1, GLUT1, declining, decreased significantly, The expression of GLUT1 on the surface of macrophages also decreased significantly. This indicated that acetic acid inhibited LPS induced glycolysis and glucose consumption in BMDM, suggesting that acetic acid inhibited the expression of key enzymes in glycolysis after LPS stimulation. After incubating IFN- gamma or GM-CSF to increase the glycolysis of BMDM, the release of TNF- alpha and IL-6 in the acetic acid group decreased and G was less than G. The expression of LUT1, PFKFB3, HK2, and MCT4 m RNA decreased; while the pre incubation of IFN- gamma or GM-CSF in the acetic acid treatment group, the release of TNF- alpha and IL-6 in the acetic acid group was reduced and GLUT1 was seen, and the decrease in the expression was almost completely reversed. It showed that the increase of glycolysis could reverse the anti-inflammatory effect of acetic acid. The 2-NBDG uptake of mouse spleen macrophages in the treatment group was significantly reduced, indicating that the glucose uptake induced by LPS in the body increased the role of.4.HIF-1 alpha in glycolysis: in BMDM, the expression of HIF-1 alpha m RNA and protein in LPS group increased, and the HIF-1 alpha m RNA and protein expression in the acetic acid group decreased significantly (P0.05) was statistically significant (P0.05). At the level of M RNA and the protein level of acetic acid, it inhibited the up regulation of HIF-1 alpha induced by LPS stimulation. The expression of HIF-1 alpha in BMDM was inhibited by DMOG. The results showed that TNF- alpha and IL-6 increased significantly in LPS group, and the TNF- alpha and IL-6 in the acetic acid group were significantly lower than those in the group. The -1 alpha specific vector overexpressed HIF-1 a. The results showed that the TNF- alpha and IL-6 in the LPS group increased significantly, and the TNF- alpha and IL-6 in the acetic acid treatment group were significantly lower than those in the LPS group, but the HIF-1 alpha overexpression and the TNF- alpha and IL-6 in the acetic acid group were not significantly different from those in the LPS group. 1, the expression of PFKFB3, HK2, MCT4 m RNA increased significantly, the expression of GLUT1 on the surface of macrophages increased significantly, the production of lactic acid and glucose increased significantly, and the expression of GLUT1, PFKFB3, HK2, MCT4 m RNA decreased significantly in the acetic acid group. The acid production and glucose level decreased significantly, and there was no significant difference from the LPS group. This indicated that the cytokine produced by the acetic acid reduction of LPS stimulation was at least partly regulated by the HIF-1 alpha dependent glycolysis. In BMDM, the NF- kappa B p65 phosphorylation in the LPS group increased, and the NF- kappa B p65 phosphorylation of the acetic acid group decreased. Addition, there was no significant difference from the LPS group; it was proved that DMOG could completely reverse the inhibitory effect of acetic acid on the activation of NF- kappa B. Finally, it was necessary to study in vivo that HIF-1 alpha was essential for the action of acetic acid to protect sepsis: the expression of HIF-1 a in the macrophages of sepsis mice was inhibited by DMOG in vivo, and the mortality of mice in the acetic acid group was significantly lower than that in the CLP group, and the liver lung group was significantly lower. The liver vein, central vein and hepatic sinus congestion, hepatic necrosis area and inflammatory cell infiltration decreased significantly, the capillary wall reconstruction of pulmonary vein and alveolar wall increased, pulmonary capillary hyperemia and fibrotic hyperplasia decreased. The AST of the acetic acid treatment group decreased significantly, the count of peritoneal bacteria decreased significantly; plasma IL-6, IL-1 The level of beta, TNF- alpha decreased, and the effect of acetic acid on mortality decreased obviously after DMOG pretreatment. Acetic acid improved tissue damage caused by sepsis, reduced the release of pro-inflammatory factors and enhanced the ability to scavenge the pathogen. It indicated that HIF-1 alpha plays a key role in glycolysis induced by acetic acid. Inhibition of the expression of HIF-1 alpha induced by LPS inhibits the glycolysis caused by LPS and reduces the release of proinflammatory factors, thus alleviating the organ dysfunction caused by sepsis and improving its survival rate.

【学位授予单位】：第二军医大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R459.7

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