本文選題：膿毒癥 + 心衰��； 參考：《南京醫(yī)科大學》2016年博士論文

【摘要】：目的：心功能不全是膿毒癥及膿毒性休克時常見并發(fā)癥,是危重病患者最常見的死因。近期的研究發(fā)現(xiàn)microRNAs (miRNAs)在膿毒癥中可作為標志物發(fā)揮潛在作用,但是其在膿毒性心肌病(Sepsis-induced cardiomyopathy, SIC)的作用知之甚少。本項研究將探討miRNAs在膿毒癥心肌病中可能扮演的角色,并為臨床治療膿毒癥心功能不全尋找可能的干預靶點提供理論依據(jù)。方法：C57BL/6小鼠注射脂多糖(LPS) (5mg/kg)誘導膿毒性心肌病模型,對照組給與同等劑量的生理鹽水,5-7h后測心超,7-9h收取心臟標本,進行miRNAs芯片篩選與LPS誘導膿毒性心衰相關的miRNAs。通過小鼠尾靜脈注射miRNA的激動劑和抑制劑,觀察其在LPS刺激下對心臟功能、炎癥因子、糖脂代謝、自噬等方面的影響。小鼠腹腔注射致死量脂多糖(LPS,15mg/kg),連續(xù)觀察72小時記錄miRNA抑制劑組小鼠的死亡情況。結果：在LPS注射后1h心功能開始下降,7-9h心功能達到最低,收取心臟組織進行miRNAs芯片篩選。我們發(fā)現(xiàn)8個miRNA在LPS處理后發(fā)生改變,通過進一步驗證發(fā)現(xiàn)miR-21-3p升高倍數(shù)最高,并且在LPS注射后1h即升高,與心功能呈負相關。miR-21-3p抑制劑能改善LPS導致心功能的下降、自噬增高、線粒體超微損傷和心肌肥大,并能提高小鼠的生存率；而miR-21-3p激動劑會加重以上的表現(xiàn)。Sorbin和SH3結構域連接蛋白2 (SH3 domain-containing protein 2, SORBS2)與miR-21-3p在LPS組小鼠心臟組織中存在內(nèi)源性調(diào)控關系,提示其可能是miR-21-3p的靶基因。與心功能正常的膿毒癥患者相比,膿毒癥心功能不全患者血漿中的miR-21-3p顯著升高。ROC曲線結果顯示線下面積為0.939,miR-21-3p是預測膿毒癥心功能正常與否的一個特異性指標。結論：因此,miR-21-3p是通過抑制靶基因SORBS2,在膿毒癥心肌病的發(fā)病過程中發(fā)揮著重要作用,這一結果提示miR-21-3p可能是一種治療SIC的潛在新靶點。
[Abstract]:Objective: cardiac insufficiency is a common complication of sepsis and septic shock and the most common cause of death in critically ill patients. Recent studies have found that microRNAs (miRNAs) play a potential role as markers in sepsis, but little is known about their role in septic cardiomyopathy (sic). This study will explore the role of miRNAs in septic cardiomyopathy and provide a theoretical basis for clinical treatment of septic heart failure. Methods the septic cardiomyopathy model was induced by injection of lipopolysaccharide (5mg/kg) into mice of 10% C57BL / 6 mice. The control group was given the same dose of normal saline for 5-7 h, and the heart supernatant was measured for 7-9 h. MiRNAs microarray was used to screen miRNAs associated with LPS-induced septic heart failure. The effects of miRNA agonists and inhibitors on cardiac function, inflammatory factors, glucose and lipid metabolism and autophagy were observed by injecting miRNA into tail vein of mice. The lethal dose of lipopolysaccharide (LPSN 15 mg / kg) was injected intraperitoneally to observe the death of mice in miRNA inhibitor group for 72 hours. Results: the cardiac function began to decline at 1 h after LPS injection and the cardiac function reached the lowest at 7-9 hours. The heart tissues were selected for miRNAs microarray screening. We found that eight miRNAs changed after LPS treatment. Further verification showed that miR-21-3p had the highest increase multiple, and increased at 1 hour after LPS injection, which was negatively correlated with cardiac function. MiR-21-3p inhibitor could improve the decrease of cardiac function induced by LPS and increase autophagy. Mitochondrial ultrastructure damage, myocardial hypertrophy and survival rate of mice were increased by miR-21-3p agonists, and miR-21-3p agonists increased the expression of .Sorbin, SH3 domain-containing protein 2 (SORBS2) and miR-21-3p in LPS-treated mice. It may be the target gene of miR-21-3p. Compared with sepsis patients with normal cardiac function, miR-21-3p in plasma of septic patients with cardiac insufficiency increased significantly. The results of ROC curve showed that the area under line was 0.939 mil R-21-3p, which was a specific index to predict the normal heart function of sepsis. Conclusion: miR-21-3p may play an important role in the pathogenesis of septic cardiomyopathy by inhibiting the target gene SORBS2, which suggests that miR-21-3p may be a potential new target for the treatment of sic.
【學位授予單位】：南京醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R459.7;R542.2

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