本文選題：膿毒癥 + 心衰　； 參考：《南京醫(yī)科大學(xué)》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(shí)常見(jiàn)并發(fā)癥,是危重病患者最常見(jiàn)的死因。近期的研究發(fā)現(xiàn)microRNAs (miRNAs)在膿毒癥中可作為標(biāo)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(xiàng)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(yù)靶點(diǎn)提供理論依據(jù)。方法：C57BL/6小鼠注射脂多糖(LPS) (5mg/kg)誘導(dǎo)膿毒性心肌病模型,對(duì)照組給與同等劑量的生理鹽水,5-7h后測(cè)心超,7-9h收取心臟標(biāo)本,進(jìn)行miRNAs芯片篩選與LPS誘導(dǎo)膿毒性心衰相關(guān)的miRNAs。通過(guò)小鼠尾靜脈注射miRNA的激動(dòng)劑和抑制劑,觀察其在LPS刺激下對(duì)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(shí)記錄miRNA抑制劑組小鼠的死亡情況。結(jié)果：在LPS注射后1h心功能開(kāi)始下降,7-9h心功能達(dá)到最低,收取心臟組織進(jìn)行miRNAs芯片篩選。我們發(fā)現(xiàn)8個(gè)miRNA在LPS處理后發(fā)生改變,通過(guò)進(jìn)一步驗(yàn)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(fù)相關(guān)。miR-21-3p抑制劑能改善LPS導(dǎo)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(dòng)劑會(huì)加重以上的表現(xiàn)。Sorbin和SH3結(jié)構(gòu)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(guān)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(jié)果顯示線下面積為0.939,miR-21-3p是預(yù)測(cè)膿毒癥心功能正常與否的一個(gè)特異性指標(biāo)。結(jié)論：因此,miR-21-3p是通過(guò)抑制靶基因SORBS2,在膿毒癥心肌病的發(fā)病過(guò)程中發(fā)揮著重要作用,這一結(jié)果提示miR-21-3p可能是一種治療SIC的潛在新靶點(diǎn)。
[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(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：R459.7;R542.2

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