本文選題：急性肺損傷　切入點(diǎn)：過氧化物酶增殖體激活受體　出處：《大連醫(yī)科大學(xué)》2013年碩士論文

【摘要】：目的：復(fù)制失血性休克大鼠ALI模型后，觀察PPARβ在ALI肺組織的表達(dá)情況；然后采用PPARβ的激活劑（GW0742）、拮抗劑（GSK0660）、GW0742和GSK0660聯(lián)合對大鼠ALI模型進(jìn)行干預(yù)，觀察其對失血性休克大鼠ALI肺組織表達(dá)PPARβ的影響，研究PPARβ在ALI發(fā)生發(fā)展過程中的保護(hù)作用及相關(guān)機(jī)制。 方法：復(fù)制失血性休克大鼠ALI模型，按完全隨機(jī)原則將120只SD大鼠分入五組，假手術(shù)組（A組）、失血性休克致急性肺損傷模型組（B組）、GSK0660組（C組）、GW0742組（D組）和聯(lián)合組（E組）。每組分為1h、2h、4h、6h四個(gè)時(shí)相點(diǎn)，每個(gè)時(shí)相點(diǎn)6只老鼠。具體操作方法為A組僅行動(dòng)靜脈穿刺，不具備失血性休克ALI模型，同時(shí)給予靜脈注射10%DMSO3ml/kg，B組靜脈注射10%DMSO3ml/kg，30min后注射生理鹽水2.5ml/kg，之后復(fù)制血性休克大鼠ALI模型；C組先給大鼠靜脈注射GSK06603mg/Kg，30min后注射生理鹽水2.5ml/kg，復(fù)制失血性休克ALT模型。D組先給大鼠靜脈注射GW07423mg/Kg，30min后注射生理鹽水2.5ml/kg，復(fù)制失血性休克ALT模型。E組先給大鼠靜脈注射GSK0660+GW0742，兩者之間注射時(shí)間隔15min，30min后注射生理鹽水2.5ml/kg，，復(fù)制失血性休克ALI模型。觀察記錄在1、2、4、6小時(shí)取肺組織測定PPARβ受體表達(dá)，并行病理學(xué)檢查、肺中性粒細(xì)胞浸潤、肺干濕重比系數(shù)和支氣管肺泡灌洗液(BALF)中總蛋白作為檢測肺損傷程度的指標(biāo)；檢測肺組織抗氧化物酶SOD、CAT、GSH-Px活性氧化產(chǎn)物8-iso-PGF2α含量來評估機(jī)體氧化應(yīng)激狀態(tài)來評估機(jī)體氧化應(yīng)激狀態(tài)。然后，給予PPARβ受體拮抗劑進(jìn)行預(yù)處理，觀察其對失血性休克所致急性肺損傷過程中后動(dòng)物各項(xiàng)指標(biāo)的影響，并初步探討炎癥因子、氧化抗氧化系統(tǒng)及細(xì)胞凋亡在其中的作用。 結(jié)果： 1．失血性休克致傷組大鼠抗氧化物酶SOD、CAT、GSH-Px活性較假手術(shù)組顯著升高(P0.05)。 2. GW0742使ALI肺組織中抗氧化物酶SOD、CAT、GSH-Px活性在各時(shí)相點(diǎn)較單純失血性休克致傷組有不同程度降低，以2h、4h升高最顯著(P0.05)。 3、單獨(dú)使用GW0742能改善PaO2、大鼠肺組織W/D比值、肺組織病理積分，抑制肺組織SOD、 CAT、 GSH-Px活性(P0.05)及降低8-iso-PGF2α的含量；使用拮抗劑GSK0660使上述作用減輕(P0.05)。 結(jié)論： 1、失血性休克ALI大鼠模型，肺組織SOD、CAT、GSH-Px活性顯著升高，提示失血性休克處于急性氧化應(yīng)激狀態(tài)。 2、GW0742能顯著上調(diào)ALI大鼠肺組織SOD、CAT、GSH-Px的活性，降低氧化產(chǎn)物8-iso-PGF2α的含量。 3、推測GW0742通過可能通過抑制TNF-α基因和蛋白的表達(dá)，降低肺組織SOD活性對ALI肺組織起到一定程度的保護(hù)作用，減輕ALI肺組織的炎癥，改善PaO2，可能是通過阻止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 偽) 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 偽 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 偽 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- 偽 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.
【學(xué)位授予單位】：大連醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2013
【分類號】：R459.7

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