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HIF-1α在海水淹溺性肺損傷機(jī)制中作用的研究

發(fā)布時(shí)間:2018-06-13 20:02

  本文選題:海水淹溺 + 滲透壓; 參考:《第四軍醫(yī)大學(xué)》2012年碩士論文


【摘要】:研究背景:淹溺是一個(gè)重大公共衛(wèi)生問題,淹溺性肺損傷是淹溺對機(jī)體造成的最主要的傷害之一,其中海水淹溺性肺損傷較淡水淹溺肺損傷更為嚴(yán)重,也更容易發(fā)展成為急性呼吸窘迫綜合癥,目前還沒有關(guān)于海水淹溺肺損傷機(jī)制所特有的比較系統(tǒng)的理論。肺組織缺氧環(huán)境是海水淹溺性肺損傷與其它急性肺損傷(如缺氧性肺損傷和LPS導(dǎo)致的肺損傷)所共有的特點(diǎn),而高滲環(huán)境是海水淹溺性肺損傷所特有的影響因素,海水淹溺肺損傷中同時(shí)存在缺氧和高滲因素,而這兩個(gè)因素又都可能影響肺組織的HIF-1α表達(dá),同時(shí)鑒于HIF-1α在炎癥反應(yīng)和肺血管通透性變化中的重要作用,因此本課題著重研究了HIF-1α在海水淹溺性肺損傷機(jī)制中的作用。 目的:研究HIF-1α在海水淹溺性肺損傷機(jī)制中的作用。 方法:SD大鼠隨機(jī)分成6組,每組8只,分別用海水(1300mOsm/kgH2O)、高滲山梨醇(1300mOsm/kgH2O)、等滲海水(300mOsm/kgH2O)、等滲山梨醇(300mOsm/kgH2O)和淡水(0mOsm/kgH2O)氣管內(nèi)緩慢滴入,并設(shè)立空白對照組(只麻醉并暴露氣管不滴入液體),各組滴入液體保持相同的溫度(25℃)和pH值(8.2)。分別在指定時(shí)間點(diǎn)測量每組大鼠PaO2、PaCO2以及肺組織炎癥因子(TNF-α、IL-1β和IL-6)含量、支氣管肺泡灌洗液(BALF)白細(xì)胞計(jì)數(shù)、肺血管通透性、肺組織濕/干重比值(W/D)、肺組織HIF-1α和VEGF蛋白及mRNA含量。另外,分別用海水(1300mOsm/kgH2O)、高滲山梨醇溶液(1300mOsm/kgH2O)、高滲白蛋白溶液(1300mOsm/kgH2O)和雙蒸水(0mOsm/kgH2O)處理NR8383細(xì)胞,各組溶液保持相同的溫度(25℃)和pH值(8.2),觀察不同滲透壓梯度和時(shí)間點(diǎn)下NR8383細(xì)胞HIF-1α蛋白和mRNA含量變化,并觀察缺氧和高滲聯(lián)合作用對上述細(xì)胞HIF-1α蛋白和mRNA含量變化的影響。此外,應(yīng)用ATM、PI3K、p38的抑制劑KU55933、LY294002、SB203580及CHX研究高滲調(diào)節(jié)HIF-1α表達(dá)的可能機(jī)制。最后,應(yīng)用HIF-1α的小干擾RNA技術(shù)和測量單層細(xì)胞通透性的方法研究高滲環(huán)境下HIF-1α在炎癥反應(yīng)和肺血管通透性調(diào)節(jié)中的作用。 結(jié)果:用高滲液體(海水和高滲山梨醇)氣管內(nèi)滴入組大鼠肺組織缺氧、炎癥因子水平、肺血管通透性、肺水腫都明顯高于用等滲和低滲液體(等滲海水、等滲山梨醇和淡水)滴入組,同時(shí)伴有HIF-1α和VEGF蛋白及mRNA含量的明顯增加。在NR8383細(xì)胞上證明了是海水中的高滲因素而不是離子、溫度、pH值等其它因素導(dǎo)致的HIF-1α蛋白和mRNA含量的增加;同時(shí),發(fā)現(xiàn)高滲和缺氧可以協(xié)同作用增加HIF-1α蛋白。此外,實(shí)驗(yàn)表明高滲通過增加ATM和PI3K的磷酸化水平上調(diào)了HIF-1α mRNA的表達(dá)進(jìn)而使HIF-1α蛋白含量增加,并且通過增加p38的磷酸化水平抑制了HIF-1α蛋白的降解進(jìn)而使可檢測到的HIF-1α蛋白含量增加。最后,我們驗(yàn)證了高滲環(huán)境下HIF-1α促進(jìn)NR8383細(xì)胞產(chǎn)生炎癥因子,同時(shí)HIF-1α通過增加VEGF蛋白表達(dá)使RLMVEC單層細(xì)胞通透性增加。 結(jié)論:海水淹溺導(dǎo)致的肺部高滲和缺氧環(huán)境協(xié)同增加了肺組織HIF-1α表達(dá),,增加了的HIF-1α通過提高肺組織炎癥因子水平和肺血管通透性進(jìn)而加重了肺部炎癥反應(yīng)和肺水腫。
[Abstract]:Background: drowning is a major public health problem. Drowning lung injury is one of the most important injuries caused by drowning, in which seawater drowning lung injury is more serious than that of fresh water drowning, and it is more likely to develop into acute respiratory distress syndrome. The hypoxic environment of lung tissue is the common characteristic of seawater drowning lung injury and other acute lung injury (such as hypoxic lung injury and LPS induced lung injury), while hypertonic environment is a special factor in seawater drowning lung injury, and there are also hypoxia and hypertonic factors in seawater drowning injury. The two factors may also affect the expression of HIF-1 alpha in lung tissue, and in view of the important role of HIF-1 alpha in the changes of inflammatory response and pulmonary vascular permeability, this topic focuses on the role of HIF-1 alpha in the mechanism of seawater drowning induced lung injury.
Objective: To study the role of HIF-1 alpha in the mechanism of lung injury induced by seawater drowning.
Methods: SD rats were randomly divided into 6 groups, with 8 rats in each group, with seawater (1300mOsm/kgH2O), hypertonic sorbitol (1300mOsm/kgH2O), isosotic seawater (300mOsm/kgH2O), isososmotic sorbitol (300mOsm/kgH2O) and fresh water (0mOsm/kgH2O) endotracheal endotracheal, and an empty white control group (only anaesthetized and exposed to the liquid of the trachea). Each group was instilled in liquid. At the same temperature (25 degrees centigrade) and pH (8.2), the content of PaO2, PaCO2, inflammatory factors (TNF-, IL-1, and IL-6) in each group of rats, the white cell count, pulmonary vascular permeability, the ratio of lung tissue wet / dry weight (W/D), the HIF-1 and VEGF protein and mRNA content of lung tissue, and the concentration of HIF-1 and VEGF protein and mRNA in lung tissue were measured at the designated time points. NR8383 cells were treated with seawater (1300mOsm/kgH2O), hypertonic sorbitol solution (1300mOsm/kgH2O), hypertonic albumin solution (1300mOsm/kgH2O) and double steamed water (0mOsm/kgH2O). The solution of each group kept the same temperature (25) and pH value (8.2). The changes of HIF-1 a protein and mRNA content in NR8383 cells were observed at different osmotic pressure and time points, and the deficiency was observed. The effect of the combination of oxygen and hypertonic on the changes of HIF-1 alpha protein and mRNA in the above cells. In addition, the possible mechanism of hypertonic HIF-1 alpha expression was studied by using ATM, PI3K, p38 inhibitor KU55933, LY294002, SB203580 and CHX. Finally, the application of HIF-1 alpha's small interference RNA Technology and measurement of the permeability of monolayer cells was used to study the hypertonic environment. The role of F-1 alpha in inflammatory response and regulation of pulmonary vascular permeability.
Results: hypertonic liquid (sea water and high osmotic sorbitol) was used in the endotracheal drip of rats' lung tissue, the level of inflammatory factors, pulmonary vascular permeability, and pulmonary edema were significantly higher than that of isosmotic and hypotonic fluid (isosotic sorbitol and fresh water), accompanied by a significant increase in the content of HIF-1 alpha and VEGF protein and mRNA. In NR8383 It is shown that the hypertonic factor in the sea is not the ion, the temperature, the pH value and other factors resulting in the increase of the HIF-1 alpha protein and the mRNA content. At the same time, it is found that hypertonic and anoxia can synergistically increase the HIF-1 alpha protein. Furthermore, the experiment shows that hypertonic increases the expression of HIF-1 a mRNA by increasing the phosphorylation level of ATM and PI3K. Increase the content of HIF-1 alpha protein and inhibit the degradation of HIF-1 alpha protein by increasing the phosphorylation level of p38 and then increase the detected HIF-1 alpha protein content. Finally, we verify that HIF-1 alpha promotes the production of inflammatory factors in NR8383 cells under hypertonic environment, and HIF-1 alpha is permeable by increasing the expression of VEGF protein to make RLMVEC monolayer cells permeable. Sex increases.
Conclusion: the pulmonary hyperosmotic and anoxic environment caused by seawater drowning synergistically increased the expression of HIF-1 alpha in lung tissue, and increased HIF-1 alpha by increasing the level of inflammatory factors and pulmonary vascular permeability in lung tissue and aggravating the pulmonary inflammatory response and pulmonary edema.
【學(xué)位授予單位】:第四軍醫(yī)大學(xué)
【學(xué)位級別】:碩士
【學(xué)位授予年份】:2012
【分類號】:R649.3

【引證文獻(xiàn)】

相關(guān)期刊論文 前1條

1 華靜;馮華松;王慶;張燕;張春陽;趙麗;;海水淹溺致大鼠急性肺損傷模型的建立[J];現(xiàn)代生物醫(yī)學(xué)進(jìn)展;2013年27期

相關(guān)碩士學(xué)位論文 前1條

1 華靜;低氧誘導(dǎo)因子在海水淹溺致大鼠急性肺損傷中的作用研究[D];安徽醫(yī)科大學(xué);2013年



本文編號:2015242

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