發(fā)布時(shí)間：2018-07-05 17:57

  本文選題：心腎綜合征 + 心肌梗死��； 參考：《上海交通大學(xué)》2014年博士論文

【摘要】：背景:慢性心力衰竭和慢性腎病往往共存于同一機(jī)體內(nèi)互相影響,并導(dǎo)致了心力衰竭加重,晚期腎臟病變的進(jìn)一步惡化和預(yù)后不良。臨床研究證實(shí)了心肌梗死后的患者腎功能可發(fā)生慢性惡化,特別是那些已伴有腎功能損害的人群中,而糖尿病腎病則是這些人群的首要病因。這種慢性心力衰竭和慢性腎病共存且相互影響并導(dǎo)致病變加重的這一復(fù)雜的病理生理現(xiàn)象稱之為心腎綜合征。既往已有許多證據(jù)提示免疫激活參與了多種病因?qū)е碌哪I損害進(jìn)程,然而在心肌梗死后是否同樣參與和誘導(dǎo)了腎臟功能的損害而導(dǎo)致預(yù)后不良,即慢性心腎綜合征,及其相關(guān)機(jī)制仍無深入研究。目的:本研究旨在:1.通過建立心肌梗死合并切單腎(UNX+MI)和心肌梗死合并I型糖尿病兩個(gè)聯(lián)合損傷大鼠模型(即出現(xiàn)心腎綜合征病理生理改變),觀察其心、腎結(jié)構(gòu)與功能的改變,并比較其與單純心肌梗死大鼠相關(guān)指標(biāo)的差異;2.觀察心肌梗死12周后各組模型大鼠腎內(nèi)細(xì)胞免疫和體液免疫等指標(biāo)改變的同時(shí),觀察腎臟血流動(dòng)力學(xué)/血管反應(yīng)性,腎臟內(nèi)質(zhì)網(wǎng)應(yīng)激等改變;3.觀察Rho激酶抑制劑是否能夠改善聯(lián)合損傷模型大鼠中上述免疫機(jī)制等異常并改善心、腎功能;以進(jìn)一步探討腎臟免疫等機(jī)制是否參與了心梗后心、腎功能的進(jìn)一步損害,以及內(nèi)質(zhì)網(wǎng)應(yīng)激在慢性心腎綜合征病理生理過程中的分子作用機(jī)制和價(jià)值。方法:實(shí)驗(yàn)分組:1):假手術(shù)對(duì)照組(control,Ctr.n=12);2)冠脈結(jié)扎誘導(dǎo)的心肌梗死組(MI,n=12);3)切單腎組(UNX,n=11);4)切單腎合并心肌梗死組(UNX+MI,n=11);5)切單腎合并心肌梗死給予Fasudil治療組(UNX+MI+Fas,n=11);6)單純STZ誘導(dǎo)I型糖尿病組(DB,n=11);7)STZ誘導(dǎo)糖尿病合并心肌梗死組(DB+MI,n=11)和8)糖尿病合并心肌梗死組給予Fasudil治療組(DB+MI+Fas,n=11)。分別比較Ctr和MI(protocol 1);UNX+MI和UNX,UNX+MI+Fas(protocol 2);DB+MI和DB,DB+MI+Fas(protocol 3);以及聯(lián)合損傷模型——UNX+MI,DB+MI與單純MI組之間的心腎結(jié)構(gòu)、功能和相關(guān)病生機(jī)制的差異。以對(duì)照研究:1)切單側(cè)腎后心肌梗死對(duì)心臟和腎臟功能的進(jìn)一步損害;2)伴有糖尿病腎病是否加重心肌梗死對(duì)心腎功能的影響;3)通過電子顯微鏡,流式細(xì)胞儀,免疫組化,免疫熒光以及多導(dǎo)myograph系統(tǒng)等檢測(cè)手段觀察各組大鼠的心、腎結(jié)構(gòu)和腎局部免疫、血流動(dòng)力學(xué)和內(nèi)質(zhì)網(wǎng)應(yīng)激等機(jī)制的異常;4)觀察Fasudil治療是否通過改善免疫細(xì)胞的侵潤和免疫復(fù)合物的沉積以及腎臟內(nèi)質(zhì)網(wǎng)應(yīng)激而改善CRS中的腎臟功能。結(jié)果:第一部分:心梗12周后各組大鼠心、腎結(jié)構(gòu)和功能的改變1)心功能:心梗12周后,心超(LVEDD,LVESD,FS)及導(dǎo)管(dp/dt max,dp/dt min,LVEDP)檢測(cè)的各項(xiàng)心臟結(jié)構(gòu)和功能指標(biāo)以及血漿BNP等均顯示各模型大鼠心功能發(fā)生了一定的惡化。但聯(lián)合模型組(UNX+MI及DB+MI)較單純心梗組的改變并不一致:一方面UNX+MI及DB+MI組的血漿BNP值顯著高于單純MI組,導(dǎo)管檢測(cè)也顯示DB+MI組較單純MI組的心功能更差。但另一方面,切單腎合并心梗組較MI組的導(dǎo)管和心超參數(shù)并未顯示出顯著的差異。2)Rho信號(hào)通路的改變:聯(lián)合模型組(UNX+MI及DB+MI組)的Rho信號(hào)途徑顯著上調(diào)——p-ERM/t-ERM的比值上調(diào),fasudil則改善了其p-ERM/t-ERM的比值。3)腎功能:腎結(jié)構(gòu)和功能的檢測(cè)顯示:心梗12周后不同程度的加重了腎組織纖維化(MASSON,TGF-β),腎小球硬化(PAS),足細(xì)胞損傷(nephrin,desmin),微量白蛋白尿,且聯(lián)合模型組的腎微結(jié)構(gòu)和功能的惡化較單純MI組更顯著,Fasudil改善了UNX+MI組及DB+MI組的腎微結(jié)構(gòu)和功能的異常。第二部分:心梗12周后各組大鼠血流動(dòng)力學(xué)和血管活性的改變心梗12周后聯(lián)合模型組——UNX+MI及DB+MI組的腎灌注壓,腎葉間小動(dòng)脈收縮反應(yīng)性,腎靜脈壓,腎重/體重比等均發(fā)生顯著異常,顯示該兩個(gè)模型同時(shí)存在腎缺血和淤血,且較單純MI組更為顯著,而MI組則未顯示出與Ctr組的差異。Fasudil改善了聯(lián)合模型組的腎靜脈壓、腎重/體重比及腎葉間小動(dòng)脈的收縮反應(yīng)性。第三部分:心梗12周后各組大鼠腎臟內(nèi)質(zhì)網(wǎng)應(yīng)激的激活心梗12周后各種模型大鼠腎內(nèi)質(zhì)網(wǎng)應(yīng)激標(biāo)志物CHOP,GRP78的表達(dá)均有所增加,且聯(lián)合模型組——UNX+MI組及DB+MI組較單純MI組更為顯著。免疫組化顯示內(nèi)質(zhì)網(wǎng)應(yīng)激發(fā)生的主要部位在腎小球,而Fasudil改善了聯(lián)合模型組的腎小球內(nèi)質(zhì)網(wǎng)應(yīng)激。第四部分:心梗12周后各組大鼠腎臟免疫應(yīng)答的改變1)腎臟免疫細(xì)胞的浸潤:流式細(xì)胞儀檢測(cè)顯示心梗加重了各模型大鼠腎臟單核細(xì)胞的浸潤(KMNCs)。聯(lián)合損傷模型組——UNX+MI及DB+MI組較單純MI組的免疫細(xì)胞浸潤更為顯著,并且腎CD3+/KMNCs,CD4+/CD3+,也分別較其假手術(shù)組和單純心梗組更為顯著。此外免疫組化顯示上述免疫細(xì)胞浸潤的部位主要在腎小球。2)腎小球免疫復(fù)合物沉積:電鏡顯示聯(lián)合模型組腎小球系膜區(qū)出現(xiàn)了高電子密度物質(zhì)的沉積,免疫熒光檢測(cè)顯示其主要成分為免疫復(fù)合物Ig G和補(bǔ)體C4。同時(shí),腎浸潤的CD4+T細(xì)胞的比重和Ig G沉積量與微量白蛋白尿及血漿BNP呈一定的正相關(guān)性。3)免疫應(yīng)答與炎癥反應(yīng):流式細(xì)胞儀檢測(cè)顯示心梗12周后各組模型腎內(nèi)浸潤的產(chǎn)炎癥因子IFN-γ,IL-4的CD4+T細(xì)胞的比例顯著增加,此外,在UNX+MI組及DB+MI組產(chǎn)炎癥因子IL-17的CD4+T細(xì)胞,Treg細(xì)胞進(jìn)一步上調(diào),而Treg/Th17比例下調(diào)提示免疫相關(guān)性炎癥參與了該疾病的進(jìn)程。此外,Fasudil改善了聯(lián)合模型組中免疫細(xì)胞的浸潤和免疫復(fù)合物的沉積。結(jié)論:心肌梗死誘導(dǎo)的慢性心力衰竭加重了腎臟結(jié)構(gòu)和功能損傷,特別是在獨(dú)腎及有糖尿病腎損害的大鼠模型中,其主要的機(jī)制可能是腎細(xì)胞和體液免疫的激活,而伴隨的血流動(dòng)力學(xué)/血管反應(yīng)性和內(nèi)質(zhì)網(wǎng)應(yīng)激可能也參與了其中的進(jìn)程,Rho激酶抑制劑改善了上述機(jī)制和心、腎功能的異常。
[Abstract]:Background: chronic heart failure and chronic kidney disease often coexist with each other in the same body, resulting in exacerbation of heart failure, further deterioration of advanced renal disease and poor prognosis. Clinical studies have confirmed chronic deterioration of renal function in patients with myocardial infarction, especially among those with renal impairment, Diabetic nephropathy is the leading cause of these people. This complex pathophysiological phenomenon, which coexists with chronic renal failure and chronic kidney disease and causes aggravation of the disease, is called cardio renal syndrome. There is a lot of evidence that immune activation is involved in the process of renal damage caused by multiple causes, but in myocardial infarction The purpose of this study is: 1. the purpose of this study was to establish two combined injured rat models of myocardial infarction combined with single kidney (UNX+MI) and myocardial infarction combined with I type glycan disease (that is, the synthesis of heart and kidney syndrome) The changes of the heart, the structure and function of the kidney were observed, and the differences in the related indexes of the rats with simple myocardial infarction were compared. 2. the changes in the renal cell immunity and humoral immunity of each model rats after 12 weeks of myocardial infarction were observed, and the renal hemodynamic / vascular reactivity, and the renal endoplasmic reticulum stress were observed. 3. to observe whether the Rho kinase inhibitor can improve the abnormality of the above-mentioned immune mechanism in the combined injury model rats and improve the heart and kidney function, to further explore whether the mechanism of renal immunity is involved in the further damage of the post infarction heart, the renal function, and the molecules of endoplasmic reticulum stress in the pathophysiological process of chronic heart and kidney syndrome. Effect mechanism and value. Methods: experimental group: 1): control (Ctr.n=12); 2) coronary artery ligation induced myocardial infarction (MI, n=12); 3) single kidney group (UNX, n=11); 4) single kidney combined with myocardial infarction (UNX+MI, n=11); 5) single kidney combined with myocardial infarction (UNX+MI+Fas, n=11); 6) simple STZ induced diabetic diabetes mellitus The disease group (DB, n=11); 7) STZ induced diabetes combined with myocardial infarction (DB+MI, n=11) and 8) diabetes combined with myocardial infarction group was given Fasudil treatment group (DB+MI+Fas, n=11). Differences in cardiac and renal structure, function and related pathogenesis between groups. Control study: 1) further impairment of unilateral post renal infarction on cardiac and renal function; 2) whether diabetic nephropathy aggravates myocardial infarction on cardiac and renal function; 3) through electronic microscopes, flow cytometry, immunohistochemistry, immunofluorescence, and multi conductance Myograph system and other detection methods observe the heart, renal structure and local immune, hemodynamics and endoplasmic reticulum stress in rats. 4) observe whether Fasudil treatment improves the renal function in CRS by improving the deposition of immune cells and the deposition of immune complex and renal endoplasmic reticulum. Results: the first part: Heart, renal structure and function change 1) cardiac function after 12 weeks of myocardial infarction. After 12 weeks of myocardial infarction, Cardiac Ultrastructure and function indexes, such as dp/dt max, dp/dt min, LVEDP and dp/dt max, dp/dt min, LVEDP, and plasma BNP all showed that the cardiac function of each model rats had been deteriorated, but the combined model group (UNX+MI and DB+MI) was compared. The changes in the simple myocardial infarction group were not consistent: on the one hand, the plasma BNP value of the UNX+MI and DB+MI groups was significantly higher than that in the simple MI group. The catheter detection also showed that the cardiac function of the DB+MI group was worse than that in the simple MI group. On the other hand, the single renal combined myocardial infarction group had no significant difference in the Rho signaling pathway from the catheter and cardiac parameters of the MI group: the change of the Rho signaling pathway. The Rho signal pathway in the combined model group (UNX+MI and DB+MI) was significantly up-regulated, the ratio of p-ERM/t-ERM was up, and fasudil improved the p-ERM/t-ERM ratio.3) renal function. The renal structure and function test showed that renal tissue fibrosis (MASSON, TGF- beta), glomerulosclerosis (PAS), and foot cell injury (nephrin) were aggravated after 12 weeks of myocardial infarction. Desmin), microalbuminuria, and the deterioration of renal microstructures and functions in the combined model group was more significant than that in the simple MI group. Fasudil improved the renal microstructures and function abnormalities in group UNX+MI and DB+MI group. The second part: the changes of hemodynamics and vasoactivity in each group after 12 weeks of myocardial infarction, the combined model group after 12 weeks of myocardial infarction - UNX+MI and DB+M The renal perfusion pressure in the I group, the contractile responsiveness of the interlobular arteriole, the kidney static pulse pressure, the kidney weight / weight ratio, and so on, showed that the two models had renal ischemia and congestion at the same time, which was more significant than that in the simple MI group, while the MI group did not show the difference from the Ctr group. The renal vein pressure, the kidney weight / weight ratio and the ratio of the renal weight / weight ratio in the combined model group were improved by.Fasudil. The contractile responsiveness of the interlobular arteriole of the renal interlobular. Third: after 12 weeks of myocardial infarction, the activation of the renal endoplasmic reticulum stress in each group was 12 weeks after 12 weeks. The expression of CHOP and GRP78 in the renal endoplasmic reticulum was increased, and the combined model group - the group UNX+MI and the DB+MI group were more significant than the simple MI group. Immunohistochemistry showed the endoplasmic reticulum The main part of stress occurred in the glomerulus, and Fasudil improved the glomerular endoplasmic reticulum stress in the combined model group. The fourth part: changes in renal immune response in each group after 12 weeks of myocardial infarction 1) the infiltration of renal immune cells: flow cytometry showed that the myocardial infarction aggravated the infiltration of mononuclear cells in the kidney of each model rat (KMNCs). In the injury model group, the immune cell infiltration in the UNX+MI and DB+MI group was more significant than that in the simple MI group, and the renal CD3+/KMNCs and CD4+/CD3+ were more significant than those in the sham operation group and the simple myocardial infarction group. In addition, the immunohistochemical staining showed that the site of the immune cell infiltration was mainly in the glomerular.2) glomerular immune complex deposition: the electron microscopy showed the combination of the immune cells. In the glomerular mesangial region of the model group, high electron density materials were deposited. Immunofluorescence detection showed that the main components were immune complex Ig G and complement C4., the proportion of CD4+T cells in the renal infiltration and the Ig G deposition and the positive correlation.3 in microalbuminuria and plasma BNP: the immune response and inflammatory response: flow cytometry After 12 weeks of myocardial infarction, the proportion of inflammatory factors IFN- gamma and IL-4 CD4+T cells increased significantly in each group of intrarenal infiltration. In addition, Treg cells were further up-regulated in group UNX+MI and DB+MI group of CD4+T cells producing inflammatory factor IL-17, and the downregulation of Treg/Th17 suggested that immune phase inflammation was involved in the process of the disease. In addition, Fasudil, Fasudil. Conclusion: chronic heart failure induced by myocardial infarction aggravates renal structural and functional damage, especially in the rat model of kidney and diabetic kidney damage, the main mechanism may be the activation of renal cell and humoral immunity, accompanied by blood flow. Kinetics / vascular reactivity and endoplasmic reticulum stress may also be involved in the process. Rho kinase inhibitors have improved the above mechanisms and cardiac and renal dysfunction.
【學(xué)位授予單位】：上海交通大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R542.22;R692

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