本文關鍵詞： 狼瘡性腎炎 腎小管間質(zhì)病變 P-選擇素 磁共振功能成像　出處：《上海交通大學》2015年博士論文　論文類型：學位論文

【摘要】：狼瘡性腎炎(LN)是我國最常見的繼發(fā)性腎小球腎炎之一,主要臨床表現(xiàn)為蛋白尿、血尿,嚴重者可出現(xiàn)腎病綜合征,甚至腎功能不全。2003年國際腎臟病協(xié)會和腎臟病理組織(ISN/RPS)主要依據(jù)腎小球病變情況對LN進行了分型。事實上,60%~70%LN患者可出現(xiàn)不同程度的腎小管損害、腎間質(zhì)炎癥和纖維化,而且腎小管間質(zhì)病變的嚴重程度直接影響了LN的進展速度和預后。在LN的小管間質(zhì)病變發(fā)生過程中,免疫損傷可能導致腎血管內(nèi)皮細胞活化、組織缺血缺氧,腎內(nèi)活性氧(ROS)大量產(chǎn)生,在ROS、P-選擇素以及促分裂素原活化蛋白激酶作用下中性粒細胞聚集粘附,進而加重了腎小管間質(zhì)損傷。細胞黏附分子P-選擇素主要表達在活化的血小板/內(nèi)皮細胞表面,是在炎癥早期介導中性粒細胞于血管內(nèi)皮滾動和初始黏附的關鍵成分,可促使炎癥部位中性粒細胞募集,在LN小管間質(zhì)病變中可能起到重要作用。本研究利用磁共振(MR)功能成像方法觀察經(jīng)P-選擇素單克隆抗體治療前后LN動物模型(MRL/lpr小鼠)腎臟的功能、缺氧狀態(tài)和病理變化,探討LN腎小管間質(zhì)病變的病理機制以及P-選擇素單抗對LN的早期干預和治療作用,同時探討MR功能成像在狼瘡性腎炎腎臟病變、氧合水平的動態(tài)監(jiān)測和療效評估方面的價值。研究的第一部分對65例LN患者和16例健康志愿者進行了腎臟擴散加權(quán)成像(DWI)及血氧水平依賴法(BOLD)成像。分析LN患者的腎臟表觀擴散系數(shù)(ADC)和表觀自旋-自旋弛豫率(R2*)值與臨床指標和病理改變的關系。結(jié)果發(fā)現(xiàn)LN腎臟的ADC值為(2.40±0.25)x10-3mm2/s,皮、髓質(zhì)R2*值分別為11.03±1.60/sec和14.05±3.38/sec,均顯著低于正常腎臟測值(分別P=0.048,P=0.045和P=0.008)。LN腎臟ADC值與eGFR顯著相關(r=0.510,P0.01),與腎臟病理慢性指數(shù)呈負相關(r=-0.249,P0.05)。髓質(zhì)R2*值與24小時尿蛋白、腎小管間質(zhì)病變程度均呈負相關(r分別為-0.244和-0.242,P0.05)。65例LN患者中16例經(jīng)過9~12個月免疫誘導治療后再次行MR功能成像,發(fā)現(xiàn)完全緩解者腎臟ADC值和R2*值較前顯著升高。研究表明DWI成像和BOLD成像檢查為動態(tài)監(jiān)測LN腎功能損害和腎組織病理改變提供了一種無創(chuàng)性方法,可能為臨床干預的療效評價提供依據(jù)。研究的第二部分以自發(fā)性LN模型MRL/lpr小鼠作為研究對象,其尿蛋白、血清肌酐、抗ds-DNA抗體均顯著高于對照組C57BL/6小鼠,自12周齡起腎小球系膜細胞增生、基底膜增厚,腎小管上皮細胞脫落,腎間質(zhì)炎細胞浸潤,尤其是血管周圍炎細胞大量聚集。采用免疫組化、Western blot方法發(fā)現(xiàn)在LN模型小鼠腎組織中有缺氧探針HypoxyprobeTM-1、缺氧標志物HIF-1α和對組織缺氧有保護作用的HO-1蛋白廣泛分布,并與腎小管間質(zhì)病變密切相關,MR功能成像腎臟ADC值與尿蛋白、血肌酐呈負相關,平均R2*值與尿蛋白、腎小管間質(zhì)病變程度及腎組織缺氧指標表達均呈負相關。結(jié)果提示腎內(nèi)缺氧是導致LN腎小管間質(zhì)病變的關鍵因素之一,功能MRI可反映LN腎臟病變及腎內(nèi)缺氧情況。研究的第三部分采用免疫組化、Western blot和實時熒光定量PCR方法發(fā)現(xiàn)LN小鼠腎組織中P-選擇素蛋白和m RNA表達顯著上調(diào)。采用P-選擇素單抗對MRL/lpr小鼠進行早期干預,缺氧探針HypoxyprobeTM-1、HIF-1α和HO-1蛋白分布和mRNA表達較未干預組和生理鹽水對照組均下降,且腎小管間質(zhì)病變的嚴重程度減輕。MR功能成像R2*值與腎小管間質(zhì)病變程度及腎組織缺氧指標表達均呈負相關。提示P-選擇素在LN腎組織表達上調(diào),可能參與啟動LN腎小管間質(zhì)早期的炎癥反應和病理損傷,BOLD-MRI可動態(tài)監(jiān)測LN干預前后腎內(nèi)氧合狀態(tài)�？傊�,本研究表明腎內(nèi)缺氧可能是導致LN腎小管間質(zhì)病變的一個關鍵因素,P-選擇素單抗干預可改善LN腎內(nèi)缺氧及腎小管間質(zhì)病變程度,功能MRI為動態(tài)監(jiān)測LN腎臟病變、氧合水平和療效評價提供了一種無創(chuàng)性方法,對于臨床上LN的早期診治、療效監(jiān)測和預后評估具有重要意義。
[Abstract]:Lupus nephritis (LN) is one of the most common secondary glomerulonephritis in our country, the main clinical manifestations were proteinuria, hematuria, serious person can appear in nephrotic syndrome, and renal insufficiency in.2003 international society of Nephrology and renal pathology (ISN/RPS) mainly on the basis of glomerular lesions were divided into type of LN. In fact, 60%~70%LN can occur in patients with renal tubular injury and renal interstitial inflammation and fibrosis, and the severity of tubulointerstitial changes directly affect the progression and prognosis of LN. In the process of quality LN tubule lesions, immune injury may lead to renal vascular endothelial cell activation, organization hypoxia ischemia, active oxygen in the kidney (ROS) produced in ROS, P-, P-selectin and mitogen activated protein kinase in neutrophil adhesion and aggregation effect, aggravate tubulointerstitial injury. Cell adhesion molecule P- selectin is mainly expressed on the surface of activated platelet / endothelial cells, is a key ingredient in the early stage of inflammation mediated neutrophil adhesion to vascular endothelial rolling and initial, can promote inflammation neutrophil recruitment, LN in tubulointerstitial lesions may play an important role. This study used magnetic resonance (MR) functional imaging method to observe the P- element before and after monoclonal antibody in LN animal model (MRL/lpr mouse) renal function status and pathological changes of hypoxia, early intervention and treatment effect of LN on renal tubule pathological lesions and mechanism of P- selectin monoclonal antibody on LN, at the same time to explore the functional MR imaging in renal lesions of lupus nephritis dynamic monitoring and evaluation, effect of oxygenation value. The first part of the study of 65 LN patients and 16 healthy volunteers were renal diffusion weighted imaging (DWI) and blood oxygen level dependent Lai (BOLD) imaging method. Analysis of apparent diffusion coefficient in patients with kidney LN (ADC) and apparent spin spin relaxation rate (R2*) value and clinical indicators and pathological changes. The results showed that LN kidney ADC value (2.40 + 0.25) x10-3mm2/s, skin, medulla R2* = 11.03 1.60 + /sec and 14.05 + 3.38/sec were significantly lower than that of normal renal values (respectively P=0.048, P=0.045 and P=0.008).LN renal ADC value was significantly correlated with eGFR (r=0.510, P0.01), and negatively correlated with renal pathological chronic index (r=-0.249, P0.05). The R2* values of medulla and urine protein of 24 hours, the degree of renal tubule matter lesions were negatively correlated (r = -0.244 and -0.242, P0.05).65 LN patients in 16 cases after 9~12 months after treatment again for MR induced immune function imaging, found complete remission of renal ADC and R2* values significantly increased. The research showed that DWI and BOLD as imaging examination for dynamic monitoring LN renal function Changes of renal pathological damage and provides a noninvasive method, may provide the basis for the evaluation of curative effect for clinical intervention. The second part of the study on spontaneous LN model MRL/lpr mice as the research object, the urine protein, serum creatinine, anti ds-DNA antibodies were significantly higher than the control group of C57BL/6 mice, the proliferation of mesangial cells from at the age of 12 weeks, basement membrane thickening, renal tubular epithelial cell shedding, renal interstitial infiltration of inflammatory cells, especially the large accumulation of perivascular inflammatory cells. Immunohistochemical method, Western blot found that hypoxia probe HypoxyprobeTM-1 in renal tissue of LN mice, hypoxia marker HIF-1 alpha and has a protective effect on hypoxia HO-1 protein is widely distributed, and tubulointerstitial lesions are closely related, MR functional imaging of renal ADC value and urinary protein was negatively correlated with serum creatinine, the average value of R2* and urinary protein, renal tubular interstitial lesion Hypoxia index and renal tissue expression showed a negative correlation. The results showed that renal hypoxia is one of the key factors leading to mass lesions of the LN renal tubule function, MRI can reflect the renal lesions and renal hypoxia LN. The third part of the study by immunohistochemistry, Western blot and real-time fluorescence quantitative PCR method found that P- selectin m RNA and protein expression was significantly up-regulated in renal tissue of LN mice. The P- selectin monoclonal antibody for early intervention of MRL/lpr mice, hypoxia probe HypoxyprobeTM-1, expression of HIF-1 and HO-1 protein distribution and mRNA than those in the untreated group and saline control group were decreased, and the severity of renal tubulointerstitial lesions reduce functional.MR imaging R2* the value of renal tubule and hypoxia index matter lesions and renal tissue expression were negatively correlated. P- selectin in renal LN expression may be involved in the early start LN tubulointerstitial inflammation And the pathological injury and BOLD-MRI dynamic monitoring of LN before and after the intervention of renal oxygenation. In conclusion, this study shows that hypoxia may lead to LN in renal tubulointerstitial lesions is one of the key factors, P- selectin monoclonal antibody intervention can improve the severity of renal LN hypoxia and renal tubule function, MRI LN kidney disease dynamic monitoring, evaluation of the oxygenation level and curative effect provides a noninvasive method for early diagnosis and treatment of clinical LN, has important significance for evaluation of curative effect monitoring and prognosis.

【學位授予單位】：上海交通大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R593.242

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