过氧化物酶增殖体激活受体β对失血性休克大鼠急性肺损伤的保护作用及机制研究

发布时间：2018-03-31 17:16

本文选题：急性肺损伤　切入点：过氧化物酶增殖体激活受体　出处：《大连医科大学》2013年硕士论文

【摘要】：目的：复制失血性休克大鼠ALI模型后，观察PPARβ在ALI肺组织的表达情况；然后采用PPARβ的激活剂（GW0742）、拮抗剂（GSK0660）、GW0742和GSK0660联合对大鼠ALI模型进行干预，观察其对失血性休克大鼠ALI肺组织表达PPARβ的影响，研究PPARβ在ALI发生发展过程中的保护作用及相关机制。方法：复制失血性休克大鼠ALI模型，按完全随机原则将120只SD大鼠分入五组，假手术组（A组）、失血性休克致急性肺损伤模型组（B组）、GSK0660组（C组）、GW0742组（D组）和联合组（E组）。每组分为1h、2h、4h、6h四个时相点，每个时相点6只老鼠。具体操作方法为A组仅行动静脉穿刺，不具备失血性休克ALI模型，同时给予静脉注射10%DMSO3ml/kg，B组静脉注射10%DMSO3ml/kg，30min后注射生理盐水2.5ml/kg，之后复制血性休克大鼠ALI模型；C组先给大鼠静脉注射GSK06603mg/Kg，30min后注射生理盐水2.5ml/kg，复制失血性休克ALT模型。D组先给大鼠静脉注射GW07423mg/Kg，30min后注射生理盐水2.5ml/kg，复制失血性休克ALT模型。E组先给大鼠静脉注射GSK0660+GW0742，两者之间注射时间隔15min，30min后注射生理盐水2.5ml/kg，，复制失血性休克ALI模型。观察记录在1、2、4、6小时取肺组织测定PPARβ受体表达，并行病理学检查、肺中性粒细胞浸润、肺干湿重比系数和支气管肺泡灌洗液(BALF)中总蛋白作为检测肺损伤程度的指标；检测肺组织抗氧化物酶SOD、CAT、GSH-Px活性氧化产物8-iso-PGF2α含量来评估机体氧化应激状态来评估机体氧化应激状态。然后，给予PPARβ受体拮抗剂进行预处理，观察其对失血性休克所致急性肺损伤过程中后动物各项指标的影响，并初步探讨炎症因子、氧化抗氧化系统及细胞凋亡在其中的作用。结果： 1．失血性休克致伤组大鼠抗氧化物酶SOD、CAT、GSH-Px活性较假手术组显著升高(P0.05)。 2. GW0742使ALI肺组织中抗氧化物酶SOD、CAT、GSH-Px活性在各时相点较单纯失血性休克致伤组有不同程度降低，以2h、4h升高最显著(P0.05)。 3、单独使用GW0742能改善PaO2、大鼠肺组织W/D比值、肺组织病理积分，抑制肺组织SOD、 CAT、 GSH-Px活性(P0.05)及降低8-iso-PGF2α的含量；使用拮抗剂GSK0660使上述作用减轻(P0.05)。结论： 1、失血性休克ALI大鼠模型，肺组织SOD、CAT、GSH-Px活性显著升高，提示失血性休克处于急性氧化应激状态。 2、GW0742能显著上调ALI大鼠肺组织SOD、CAT、GSH-Px的活性，降低氧化产物8-iso-PGF2α的含量。 3、推测GW0742通过可能通过抑制TNF-α基因和蛋白的表达，降低肺组织SOD活性对ALI肺组织起到一定程度的保护作用，减轻ALI肺组织的炎症，改善PaO2，可能是通过阻止NF-κB的活化起作用的。
[Abstract]:Objective: to observe the expression of PPAR 尾 in the lung tissue of rats with hemorrhagic shock (ALI), and to observe the expression of PPAR 尾 in the lung tissue of ALI rats, and then to use the activator of PPAR 尾, GW0742A, and the antagonist GW0742 of GSK0660 and GSK0660 to interfere with the ALI model of rats.To observe the effect of PPAR 尾 on the expression of PPAR 尾 in ALI lung tissue of hemorrhagic shock rats, and to study the protective effect of PPAR 尾 in the pathogenesis and development of ALI and its related mechanism.Methods: ALI model was established in hemorrhagic shock rats. 120 SD rats were randomly divided into five groups: sham operation group (group A), hemorrhagic shock induced acute lung injury model group (group B) and GW0742 group (group D) and combination group (group E).Each group was divided into 1 hour, 2 h and 4 h, 4 h, 4 h, 4 h, 4 h, 4 h, 4 h, 4 h, 4 h, 4 h, 4 h, 4 h, 6 mice.In group A, only venipuncture was performed without ALI model of hemorrhagic shock.At the same time, 10 DMSO 3 ml / kg B group was injected 10 DMSO 3 ml / kg g / kg group 10 DMSO 3 ml / kg L / kg group 30 minutes after injection of normal saline 2.5 ml / kg, and then the ALI model of hemorrhagic shock was induced in rats. Group C was injected with GSK06603 mg / kg / kg group 30 minutes later, then injected with normal saline 2.5 ml / kg. The ALT model of hemorrhagic shock was first given to the group D and the model of hemorrhagic shock was first given to the rat model of hemorrhagic shock. Group D was given the model of hemorrhagic shock with 2.5 ml / kg of normal saline.Rats were injected with GW07423mg / kg of normal saline 2.5 ml / kg 30 minutes later, and the hemorrhagic shock ALT model was established. Group E was injected with GSK0660 GW0742 via vein first. The rats were injected with normal saline 2.5 ml / kg after 30 minutes after the injection of GW0742.The ALI model of hemorrhagic shock was induced by the injection of GW07423 mg / kg GW0742.The model of hemorrhagic shock was induced by ALI.The expression of PPAR 尾 receptor in lung tissue was measured at 1h, 2h, 4h, and the expression of PPAR 尾 receptor was measured. The lung neutrophil infiltration, lung dry-wet weight ratio (WWR) and bronchoalveolar lavage fluid (BALF) were used as indexes to determine the severity of lung injury.The content of GSH-Px oxidation product (8-iso-PGF2 伪) in lung tissue was measured to evaluate the oxidative stress state of the body and evaluate the oxidative stress state of the body.Then, pretreatment with PPAR 尾 receptor antagonist was performed to observe the effect of PPAR 尾 receptor antagonist on the indexes of acute lung injury induced by hemorrhagic shock, and to explore the role of inflammatory factors, oxidative antioxidant system and apoptosis in the process of acute lung injury.Results:1.The activity of GSH-Px in CATH-Px of rats in hemorrhagic shock group was significantly higher than that in sham-operated group.2.The activity of GSH-Px in the lung tissue of ALI was decreased by GW0742 at different time points compared with that in the group induced by hemorrhagic shock. The highest level of GSH-Px activity was found in the lung tissue of ALI at 4 h or 4 h.(3) GW0742 alone could improve Pao _ 2, W / D ratio of lung tissue, lung pathological score, inhibit the activity of SOD, CAT, GSH-Px and decrease the content of 8-iso-PGF2 伪 in lung tissue, and the antagonist GSK0660 could alleviate the above effects.Conclusion:1. The activity of GSH-Px in the lung tissue of ALI rats with hemorrhagic shock was significantly increased, indicating that the hemorrhagic shock was in the state of acute oxidative stress.2GW0742 could significantly up-regulate the activity of GSH-Px and decrease the content of 8-iso-PGF2 伪 in the lung tissue of ALI rats.3. It is speculated that GW0742 may play a protective role in lung tissue of ALI by inhibiting the expression of TNF- 伪 gene and protein, decrease the activity of SOD in lung tissue, alleviate the inflammation of pulmonary tissue of ALI and improve PaO2, which may play a role by preventing the activation of NF- 魏 B.
【学位授予单位】：大连医科大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R459.7

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