成纤维细胞特异性蛋白-1在急性肾小管坏死病变中的表达及临床意义

目的检测成纤维细胞特异性蛋白-1(FSP-1)在急性肾小管坏死(ATN)病变肾组织及尿沉渣中的表达,并分析其临床意义。方法收集ATN患者10例,新月体肾炎2例为阳性对照,正常肾组织3例为阴性对照,采用免疫组化和免疫荧光法检测FSP-1、CD68(巨噬细胞标志物)在肾组织中的表达,并观察ATN患者尿沉渣涂片中FSP-1的表达。收集6例健康志愿者的晨尿标本作为阴性对照。结果正常肾组织肾间质小血管偶见FSP-1表达,CD68染色阴性。阳性对照新月体肾炎患者肾小球细胞性新月体及纤维细胞性新月体中FSP-1呈散在阳性分布,肾小管间质中亦可见FSP-1阳性细胞。ATN患者肾组织FSP-1阳性细胞位于损伤、再生的肾小管周围及肾小管管腔中,部分肾小管上皮细胞也见FSP-1阳性表达。肾组织病变严重的ATN患者肾脏及尿沉渣涂片中FSP-1阳性细胞明显增多。尿沉渣FSP-1阳性细胞数与肾脏FSP-1阳性细胞数呈正相关(r=0.793,P=0.006)。FSP-1与CD68的阳性表达部位不重叠。健康志愿者的尿沉渣涂片中未见FSP-1阳性细胞表达。结论 ATN患者肾组织中可见FSP-1阳性细胞的浸润及FSP-1在肾小管上皮的表达,与尿沉渣FSP-1阳性细胞数呈正相关,FSP-1有望成为反映肾小管急性损伤的生物学标志物。     

肥大细胞、巨噬细胞及转化生长因子在IgA肾病患者肾组织中的浸润及意义

目的:观察肥大细胞、巨噬细胞、转化生长因子β1在IgA肾病患者肾组织中的浸润表达,并分析其意义。方法:①收集2004-06/2006-02青岛大学医学院附属医院肾内科收治的26例IgA肾病住院患者的肾活检标本,均经肾活检确诊肾小球系膜区存在以IgA为主的免疫复合物,并经临床及实验室检查排除紫癜性肾炎、狼疮性肾炎等继发性IgA肾病,临床资料及病理资料完整,患者全部签署肾穿刺知情同意书。另取5例配型不合的移植肾或肾穿刺后病理结果正常的肾组织(捐献者均签署捐献协议)作为正常对照组。②两组标本均行常规组织化学染色及特染,采用免疫组织化学技术检测肥大细胞、巨噬细胞在肾组织中的浸润及转化生长因子β1的表达,肥大细胞与巨噬细胞阳性呈黄褐色,转化生长因子β1阳性呈深黄色。③IgA肾病活动性指标包括每系膜区系膜细胞增生数、间质炎性细胞浸润细胞性新月体占肾小球面积的百分比3项。慢性化指标包括纤维性新月体占肾小球面积、局灶性节段性硬化占肾小球面积、肾小管萎缩占肾小管间质面积、间质纤维化程度占肾小管间质面积4项。④单盲法分析肥大细胞、巨噬细胞及转化生长因子β1的相关性及其与IgA肾病活动性指标、慢性化指标、血肌酐、尿蛋白之间的关系。结果:①肥大细胞、巨噬细胞的浸润及转化生长因子β1的表达:正常肾组织中偶见或无肥大细胞、巨噬细胞和转化生长因子β1的表达,而患肾中肥大细胞、巨噬细胞的浸润数量和转化生长因子β1的表达均明显增强(t=3.82～7.27,P<0.01)。②肥大细胞、巨噬细胞、转化生长因子β1与临床指标的相关性:相应部位肥大细胞、巨噬细胞的浸润数量及转化生长因子β1的表达呈显著正相关(r=0.51～0.91,P均<0.01)。肥大细胞数量与慢性化指标、血肌酐呈显著正相关(r=0.87,0.69,P均<0.01),与活动性指标和尿蛋白定量无明显相关性(r=0.30,0.21,P均>0.05);巨噬细胞数量和转化生长因子β1与活动性指标、慢性化指标、血肌酐、尿蛋白定量均呈显著正相关(r=0.39～0.90,P均<0.01;r=0.34～0.68,P<0.01或0.05)结论:①肥大细胞可能是IgA肾病肾间质纤维化的重要参与者,其数量增加可能预示着IgA肾病的慢性化和预后不良。②巨噬细胞可能是IgA肾病发生发展过程的全程参与者,它的浸润可能是肥大细胞在肾间质中浸润的前提条件之一。③转化生长因子β1不仅是贯穿始终的重要的致纤维化因子,而且可能是巨噬细胞和肥大细胞的重要趋化因子,并能促进它们的增殖、活化、发挥生物学作用。     

肾炎康对系膜增生性肾炎大鼠肿瘤坏死因子-α和内皮素-1的影响

目的:探讨中药肾炎康治疗大鼠系膜增生性肾炎(M sPGN)的机制。方法:采用大鼠慢性血清病性M sPGN模型。于制模第6周起,肾炎康组每日灌服肾炎康口服液3 m l,模型组每日灌服等量自来水;给药42 d后,测定24 h尿蛋白定量、尿中肿瘤坏死因子α(TNFα)、内皮素1(ET 1)及肾功能,光镜下观察肾组织病理学改变。结果:模型组24 h尿蛋白、尿中TNFα、ET 1及尿素氮(BUN)、血肌酐(SC r)均显著高于正常对照组大鼠(P均<0.01);光镜下肾小球增大,弥漫性系膜增生,节段性加重,肾小球内有较多细胞浸润,肾小管有不同程度的上皮细胞浊肿及脱落,间质亦有一定程度的炎性改变。肾炎康组24 h尿蛋白、尿中TNFα、ET 1及BUN、SC r均显著低于模型组(P<0.05或P<0.01);肾脏组织病理改变较轻,系膜细胞轻度增生或呈节段性增生,肾小管病变轻微。结论:肾炎康通过抑制肾内TNFα及ET 1的合成,抑制系膜细胞增殖及肾小管间质的病理损伤,从而减少蛋白尿,保护肾功能。     

肾组织中CD80和CD86的表达及其与肾间质损伤的关系

目的探讨T淋巴细胞活化分子CD80与CD86在原发性肾小球肾炎肾小管间质损伤中的作用。方法采用免疫组织化学法检测原发性肾小球肾炎患者肾组织中的CD80与CD86的表达情况,免疫比浊法检测24h尿蛋白定量,全自动生化分析仪检测血尿素氮、血清肌酐及血浆白蛋白等临床指标。结果 CD80和CD86在原发性肾小球肾炎肾组织中的表达情况不同。CD80在肾小管上皮细胞、肾间质有阳性表达,在肾小球无表达,而CD86在肾小管上皮细胞、肾间质及肾小球均有表达。CD80和CD86在肾小管间质中的表达水平随着原发性肾小球肾炎患者肾小管间质病变程度的加重而增强(相关系数分别为0.741和0.736,P<0.001),并且CD80的表达与CD86的表达成正相关。CD80和CD86的表达与患者24h尿蛋白定量、血尿素氮和血清肌酐水平成正相关;与肌酐清除率成负相关。结论 T细胞的活化可能参与了原发性肾小球肾炎肾间质损伤。     

p16^INK4a在原发性系膜增生性肾小球肾炎的表达及意义

目的：探讨原发性系膜增生性肾小球肾炎（MsPGN）细胞周期素依赖蛋白激酶抑制剂p16^INK4a在肾小球和肾小管间质的表达分布及意义。方法：采用非生物素免疫组化二步法检测36例MsPGN患者活检肾组织肾小球和肾小管间质p16^INK4a的表达水平。结果：正常对照组肾小球见极少p16^INK4a表达,肾小管间质少许表达,MsPGN组肾小球和小管间质p16^INK4a表达升高,两组比较,具有显著统计学差异（P〈0.01）。36例病例中15例硬化、新月体形成组肾小球上高表达,而非硬化、非新月体形成组肾小球部分表达,组间相比具有显著差异（P〈0.01）,而小管间质表达无统计学差异（P〉0.05）。结论：MsPGN组p16^INK4a高表达,主要表达于硬化肾小球、新月体形成肾小球,p16^INK4a参与了MsPGN的细胞周期调控。     

p16^INK4a在原发性系膜增生性肾小球肾炎的表达及意义

目的：探讨原发性系膜增生性肾小球肾炎（MsPGN）细胞周期素依赖蛋白激酶抑制剂p16^INK4a在肾小球和肾小管间质的表达分布及意义。方法：采用非生物素免疫组化二步法检测36例MsPGN患者活检肾组织肾小球和肾小管间质p16^INK4a的表达水平。结果：正常对照组肾小球见极少p16^INK4a表达,肾小管间质少许表达,MsPGN组肾小球和小管间质p16^INK4a表达升高,两组比较,具有显著统计学差异（P〈0.01）。36例病例中15例硬化、新月体形成组肾小球上高表达,而非硬化、非新月体形成组肾小球部分表达,组间相比具有显著差异（P〈0.01）,而小管间质表达无统计学差异（P〉0.05）。结论：MsPGN组p16^INK4a高表达,主要表达于硬化肾小球、新月体形成肾小球,p16^INK4a参与了MsPGN的细胞周期调控。     

MMP-2在新月体肾小球肾炎中的表达和作用

目的：探讨MMP-2(matrix metalloproteinases-2)在新月体肾小球肾炎中的表达和作用。方法：1997-2002年问本院经肾活检证实新月体肾小球肾炎住院病人112例，其中细胞性新月体的肾活检标本60例为一组，纤维-细胞性和纤维性新月体52例为另一组。用免疫组化法测MMP-2和Ⅳ胶原蛋白表达并进行比较，并与10例正常肾组织对照。结果：MMP-2在新月体中有强表达，细胞性新月体组MMP-2蛋白表达是正常肾组织的3．2倍，而纤维-细胞性和纤维性新月体组MMP-2蛋白表达比细胞性新月体组下降了52％。Ⅳ型胶原蛋白表达是细胞性新月体组的2．1倍。重复肾活检的40例新月体肾炎病人治疗后的肾组织MMP-2蛋白表达比治疗前下降了61％。结论：新月体肾炎肾小球中过度表达MMP-2。早期治疗可抑制MMP-2表达，能及时挽救患者生命和改善预后。     

IgA肾病患者血、尿骨形成蛋白7和转化生长因子β1水平的变化及其意义

目的 观察IgA肾病患者血、尿骨形成蛋白7(BMP-7)和转化生长因子β1(TGF-β1)水平的变化并探讨其与临床指标及病理组织学指标的关系.方法 在本院肾内科住院经肾穿刺活检病理诊断为原发性IgA肾病89例.根据光镜切片病变轻重将患者分为3组:A组(轻度系膜增生性IgA肾病)47例;B组(中、重度系膜增生性IgA肾病)29例;C组(增生硬化和硬化性IgA肾病)13例.检测患者的血压、尿蛋白排泄率、血肌酐和内生肌酐清除率(CCr);用酶联免疫吸附法测定血、尿中TGF-β1和BMP-7水平;计算病理切片中硬化肾小球数、新月体数;用病理图像分析软件测定肾间质纤维化面积.结果 血、尿BMP-7浓度随着肾小球病变的加重、肾小管萎缩的增多、肾间质纤维化的增加,而逐渐降低(P<0.01);血BMP-7水平与尿BMP-7水平呈正相关(r=0.802,P<0.01);血、尿BMP-7水平与CCr呈正相关(r=0.840,P<0.01);与收缩压、舒张压、尿蛋白排泄率、硬化肾小球数、新月体数及肾间质纤维化面积呈负相关(r=-0.808、-0.783、-0.726、-0.830、-0.827、-0.815,均P<0.01);3组IgA肾病患者血、尿TGF-β1浓度随着肾小球增生程度的加重而显著升高(P<0.01);而肾小球硬化、肾小管萎缩较多、肾间质广泛纤维化时,血、尿TGF-β1浓度明显下降(P<0.01);血TGF-β1水平与尿TGF-β1水平呈正相关(r=0.792,P<0.01);血、尿TGF-β1水平与尿蛋白排泄率呈正相关(r=0.307,0.237,均P<0.05).结论 TGF-β1血、尿在IgA肾病系膜增生严重时明显增加,肾脏广泛纤维化时明显降低,可能参与了IgA肾病肾间质纤维化的发生.BMP-7血、尿随肾脏病变的加重,明显降低,可能导致其抗肾纤维化作用减弱.临床上测定血、尿BMP-7和TGF-β1水平可能可以作为判断IgA肾病患者肾脏病变进展程度的新手段之一.     

尿液标志物联合检测对狼疮肾炎小管间质损伤的预测价值

目的 评估尿液肾损伤因子1(KIM-1)、中性粒细胞明胶酶相关脂质运载蛋白(NGAL)、单核细胞趋化蛋白1(MCP-1)对狼疮肾炎(LN),特别是肾小管间质损伤的临床价值.方法 采用酶联免疫吸附试验(ELISA)法检测LN患者尿液KIM-1、NGAL、MCP-1水平,评估其与临床及病理特征的相关性,采用受试者工作特征曲线(ROC曲线)分析其诊断效能.结果 活动期LN患者KIM-1、NGAL、MCP-1水平显著高于恢复期患者及健康对照组(P<0.05);尿液KIM、NGAL与eGFR、血清肌酐、尿蛋白呈正相关(均P<0.05);患者的临床表现不同,尿液KIM-1、NGAL、MCP-1水平的升高程度不同;尿液KIM水平与活动性指数AI、细胞性新月体、毛细血管内细胞增生、小管萎缩呈正相关(P<0.05);尿液NGAL/MCP-1水平与细胞性新月体呈正相关(P<0.05);活动性肾小管间质损伤患者的尿液KIM-1、MCP-1水平显著高于慢性肾间质损伤患者(P<0.05);同时伴有活动性与慢性肾小管间质损伤的患者尿液KIM-1、NGAL、MCP-1水平显著高于仅有慢性肾小管间质损伤的患者(P<0.05).ROC曲线分析表明,3种指标联合检测可较好地预测活动性肾小管间质损伤.结论 尿液KIM-1、NGAL、MCP-1联合检测在预测肾间质损伤方面有较好的临床价值.     

法尼醇X受体在糖尿病肾病肾组织中的表达及意义

目的探讨法尼醇X受体(farnesoid X receptor,FXR)在糖尿病肾病(diabetic nephropathy,DN)肾组织中的表达及其与巨噬细胞浸润、肾损伤之间的关系。方法免疫组织化学染色观察正常肾组织(正常组,n=5)和DN肾组织(DN组,n=15)中FXR、CD68阳性细胞表达。结果 FXR主要表达在肾小球内皮细胞、系膜细胞和肾小管上皮细胞。DN肾组织FXR阳性表达积分较正常肾组织升高(P<0.01),且与CD68阳性细胞数以及血清低密度脂蛋白胆固醇和甘油三酯水平呈负相关(r分别为-0.742、-0.654、-0.632,P均<0.01),与肾小球系膜区扩张指数和肾小管-间质病变也呈负相关(r分别为-0.587、-0.636,P均<0.01),与24小时尿蛋白定量无相关性。结论 DN肾组织FXR阳性表达升高,可能参与DN炎症反应的发生,其具体表达机制和病理生理意义需要进一步研究。     

Tubulo-interstitial involvement in lupus nephritis with emphasis on pathogenesis

Glomerular lesions in lupus nephritis have been extensively studied in recent decades, but much less attention has been paid to the tubulo-interstitial compartment. The aim of this study was to contribute to the understanding of the pathogenesis of tubulo-interstitial lesions in lupus nephritis by analysing their incidence, character, and their associations. One hundred and ninety kidney biopsies of 190 patients fulfilling American Rheumatology Association (ARA) criteria of systemic lupus erythematosus (SLE) were examined by traditional light, immunofluorescence and electron microscopy. Interstitial inflammatory infiltration and tubulo-interstitial immune deposits concurred in 72 cases (37.9%). Their frequency was the highest in WHO class IV lupus glomerulonephritis. By multivariate analysis, the intensity of interstitial inflammatory infiltration correlated best with the percentage of renal corpuscules with extracapillary crescents and the extent of interstitial fibrosis. On immunohistochemical assessment, the inflammatory infiltrate was found to be composed of CD45RO positive T lymphocytes (191.3/mm2), CD68 positive macrophages (101.7/mm2) and CD45RA positive B lymphocytes (17.2/mm2). For all cell types the median value was higher in cases with extracapillary crescents, and did not correlate with presence and intensity of tubulo-interstitial immune deposits. Infiltration showed the tendency of periglomerular distribution, especially around glomeruli showing extracapillary proliferation and destruction of the capsular basal membrane. Rare S100 positive cells were only found in the interstitium. Tubulo-interstitial lesions estimated semiquantitatively correlated with the degree of proteinuria. Our findings suggest that tubulo-interstitial deposits do not play a major role in the pathogenesis of tubulo-interstitial lesions. The formation of interstitial cell infiltrates appears to be greatly influenced by the development of extracapillary crescents, perhaps by direct transmission of the severe inflammatory process to the adjacent interstitium. The composition of the infiltrate, including antigen presenting cells may signalize an additional involvement of cell-mediated immune mechanisms acting against so far hypothetical tubular epithelial neoantigens.     

54例原发ANCA相关性小血管炎的肾脏病理及预后的分析

目的探讨原发小血管炎肾脏病理特点及与肾功能预后的关系。方法 54例确诊并行肾活检的原发AN-CA相关小血管炎患者,分别按年龄及性别分组,对比统计各组病理类型和病理特点并随访。结果①肾脏病理类型检出率最高的是硬化性和轻度系膜增生性肾炎各占22.2%,其次是局灶节段硬化性肾炎（18.5%）;60岁以上组轻度系膜增生的患者比例偏高,P=0.05;②肾脏病理急慢性损害检出率较高为：中重度间质炎细胞浸润（48.1%）,中重度间质小管损害（46.3%）,纤维新月体（38.9%）,中重度增生硬化（35.2%）,细胞性新月体（24.1%）,袢坏死检出率（14.8%）;各年龄段相比,中重度增生硬化在30岁以下检出率相对较高,差异有统计学意义,P〈0.05;③随访1年,9例进入尿毒症期（16.7%）。发生尿毒症的相关风险是肾脏慢性指数,P〈0.05。结论肾小球硬化及严重的肾脏病理损害发生率高尤以年轻患者多见;发生终末期肾的相关风险因素是肾脏慢性指数。     

Expression of monocyte chemoattractant protein-1 in proximal tubular epithelial cells in a rat model of progressive kidney failure

Impairment of kidney function in various types of glomerular disease is associated with tubulointerstitial changes. Monocyte chemoattractant protein-1 (MCP-1) is up-regulated in the tubulointerstitium and in the glomeruli in many human and experimental kidney disorders. We investigated the localization of MCP-1 expression in a rat model of progressive kidney failure. Male Wistar rats were subjected to subtotal nephrectomy (n = 30) or sham surgery (n = 30). Immunohistochemistry with immunoelectron microscopy and in situ hybridization were used to examine the expression of MCP-1 protein and messenger ribonucleic acid (mRNA) in the kidney, respectively. MCP-1 protein and mRNA were hardly detected in both glomeruli and tubulointerstitium of control rats. However, in the rats subjected to nephrectomy, MCP-1 expression was increased in the tubular cells of the remnant kidney, accompanied by significant macrophage infiltration. MCP-1 was observed mainly in the proximal tubular cells and only weakly in distal tubular cells. No significant expression of MCP-1 protein or mRNA was noted in the glomeruli. Immunoelectron microscopy showed the presence of MCP-1 in the rough endoplasmic reticulum of proximal tubular cells, confirming that MCP-1 is produced in proximal tubular cells. MCP-1 was also observed in endocytic vesicles adjacent to the brush border of proximal tubular cells, suggesting incorporation of MCP-1 from the tubular lumen. Our findings indicate localized expression of MCP-1 in proximal tubular cells in the remnant kidney and suggest that MCP-1 in proximal tubular cells is involved in tubulointerstitial damage in chronic kidney failure associated with glomerular hypertension.     

The role of smooth muscle alpha-actin in development of renal fibrosis in patients with chronic glomerulonephritis

AIM: To estimate expression of smooth muscle alpha-actin (a-SMA) in renal glomeruli and interstitium of patients with chronic glomerulonephritis (CGN) for assessment of the disease progression and prognosis. MATERIAL AND METHODS: Expression of a-SMA in renal tissue was studied immunohistochemically, area of the interstitium and the degree of its interstitial inflammatory infiltration were investigated morphometrically in 45 biopsy specimens of renal tissue from patients with different morphological types of CGN and 7 specimens of normal renal tissue. RESULTS: a-SMA expression in the glomeruli was higher in patients with proliferative morphological forms of CGN [34.3% (26.1-40.6)] than in patients with nonproliferative nephritis forms [22.3% (18.5-22.3)], p < 0.001; it was the highest in patients with sclerotic alterations in the glomeruli [55.3% (37-61.8)], p < 0.01. The degree of a-SMA expression in renal interstitium of CGN patients correlated most closely with severity of tubulo-interstitial fibrosis (Rs = 0.08, p < 0.001). There was no significant correlation between glomerular a-SMA expression in renal biopsies and proteinuria, creatinine level in the serum of CGN patients, while a-SMA interstitial expression correlated both with severity of proteinuria (rs = 0.5, p < 0.05) and that of renal failure (rs = 0.7, p < 0.001). CONCLUSION: High expression of a-SMA in CGN occurs both in the glomeruli and interstitium of the kidney and evidences for activation of fibrogenesis but only interstitional expression can be considered as a morphological sign of CGN progression and as a factor of an unfavourable prognosis.     

Kallikrein-modified mesenchymal stem cell implantation provides enhanced protection against acute ischemic kidney injury by inhibiting apoptosis and inflammation

Mesenchymal stem cells (MSCs) migrate to sites of tissue injury and serve as an ideal vehicle for cellular gene transfer. As tissue kallikrein has pleiotropic effects in protection against oxidative organ damage, we investigated the potential of kallikrein-modified MSCs (TK-MSCs) in healing injured kidney after acute ischemia/reperfusion (I/R). TK-MSCs secreted recombinant human kallikrein with elevated vascular endothelial growth factor levels in culture medium, and were more resistant to oxidative stress-induced apoptosis than control MSCs. Expression of human kallikrein was identified in rat glomeruli after I/R injury and systemic TK-MSC injection. Engrafted TK-MSCs exhibited advanced protection against renal injury by reducing blood urea nitrogen, serum creatinine levels, and tubular injury. Six hours after I/R, TK-MSC implantation significantly reduced renal cell apoptosis in association with decreased inducible nitric oxide synthase expression and nitric oxide levels. Forty-eight hours after I/R, TK-MSCs inhibited interstitial neutrophil and monocyte/macrophage infiltration and decreased myeloperoxidase activity, superoxide formation, p38 mitogen-activated protein kinase phosphorylation, and expression of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1. In addition, tissue kallikrein and kinin significantly inhibited H2O2-induced apoptosis and increased Akt phosphorylation and cell viability in cultured proximal tubular cells. These results indicate that implantation of kallikrein-modified MSCs in the kidney provides advanced benefits in protection against ischemia-induced kidney injury by suppression of apoptosis and inflammation.     

Renal cell turnover studied by Y chromosome (Y body) staining of the transplanted human kidney.

To address questions about turnover between human renal cell populations and extrarenal cells, we studied kidneys that had been transplanted between sexes. By staining frozen sections with acranil and enumerating Y bodies, we could distinguish between male and female tubular and glomerular cells in control nontransplant kidneys. We studied 12 kidneys that had been transplanted from females to males, including seven which had mesangial cell hyperplasia in the transplant. There were virtually no Y body-positive nuclei in the glomeruli or tubules of the 12 kidneys. Thus there was no evidence for an extrarenal cell contribution to either normal or proliferative mesangial cells or to other renal cells. Two of these 12 kidneys had cellular glomerular crescents. Y body-postive extrarenal cells were present in the crescents. Interstitial infiltrates in female-to-male transplants were also Y body-positive.     

102例IgA肾病蛋白尿与病理临床分析

目的探讨蛋白尿对IgA肾病病理改变和临床指标的影响及其相关性。方法回顾性分析郑州大学第一附属医院肾内科102例IgA肾病患者的病理和临床资料,探讨其相关性。结果蛋白尿与牛津分型中毛细血管内增生、节段性的肾小球硬化、肾小管萎缩/间质纤维化、球性硬化、新月体病变的病理改变存在相关性,与肾功能、免疫荧光分型存在相关性,而与高血压、血清IgA、C3水平不存在相关性。结论随着蛋白尿的增多,肾脏毛细血管内增生、肾小管萎缩/间质纤维化、球性硬化等病理改变加重,且肾功能也会随之恶化。     

T cells reactive to an inducible heat shock protein induce disease in toxin-induced interstitial nephritis

T cells reactive against immunodominant regions of inducible heat shock proteins (HSPs) have been identified in the chronic inflammatory lesions of several experimental autoimmune diseases. Since HSPs are known to be induced by a number of renal tubular epithelial cell toxins associated with chronic interstitial nephritis, we investigated the relevance of HSP expression and T cell reactivity to HSP70 in a model of progressive inflammatory interstitial nephritis. Chronic administration of cadmium chloride (CdCl2) to SJL/J mice induces HSP70 expression in renal tubular cells 4-5 wk before the development of interstitial mononuclear cell infiltrates. CdCl2 also induces HSP70 expression in cultured tubular epithelial cells from SJL/J mice. CD4+, TCR-alpha/beta+ T cell lines specific for an immunodominant HSP peptide are cytotoxic to heat stressed or CdCl2-treated renal tubular cells. Such HSP-reactive T cells mediate an inflammatory interstitial nephritis after adoptive transfer to CdCl2-treated mice at a time when immunoreactive HSP70 is detectable in the kidneys, but before the development of interstitial mononuclear cell infiltrates. T cells isolated from the nephritic kidneys of mice treated with CdCl2 for 13 wk are also cytotoxic to heat shocked or cadmium-treated tubular cells. These kidney-derived T cells additionally induced interstitial nephritis after passive transfer, indicating their pathogenic significance. Our studies strongly support a role for HSP-reactive T cells in CdCl2-induced interstitial nephritis and suggest that the induction of HSPs in the kidney by a multitude of "non-immune" events may initiate or facilitate inflammatory damage by HSP-reactive lymphocytes.     

Antibodies to intercellular adhesion molecule 1/lymphocyte function- associated antigen 1 prevent crescent formation in rat autoimmune glomerulonephritis

In patients with glomerulonephritis widespread crescents are associated with a poor prognosis. Crescent formation appears to depend on the migration of mononuclear cells into Bowman's space, and therefore the interaction between leukocytes and glomerular endothelium may be a critical event in the genesis of crescents. We performed the present study to determine the effects of mouse monoclonal antibodies to the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function-associated antigen 1 (LFA-1) in a model of crescentic glomerulonephritis in Wistar-Kyoto rats, induced by immunization with bovine glomerular basement membrane (GBM). By 10-14 d after immunization, the rats had developed circulating anti-GBM antibodies, reactive with the alpha 3 chain of type IV collagen (the Goodpasture antigen), accompanied by proteinuria, accumulation of rat immunoglobulin (Ig)G in the GBM, increased expression of ICAM-1 by glomerular endothelial cells, infiltration of glomerular tufts with LFA- 1+ T cells and monocyte/macrophages, and early crescents. At 5 wk all rats had diffuse fibrocellular crescents, glomerular sclerosis, and tubulointerstitial damage. All rats developed severe renal insufficiency and died by 5 or 6 wk. The administration of monoclonal antibodies to rat ICAM-1 and LFA-1 markedly decreased the severity of the renal disease. In a group of rats injected three times a week with the monoclonal antibodies, from 2 d before immunization with GBM to day 14, glomerular abnormalities and proteinuria were virtually absent at day 14; even at 5 wk glomerular disease was quite mild, with only slight crescent formation and with only a mild decrease in renal function. When treatment was continued until 5 wk, the beneficial effects were even more marked, with virtual absence of crescents and with preservation of normal renal function. In a group of rats in which treatment was initiated on day 14, shortly after the appearance of glomerular abnormalities, progression of the disease was appreciably retarded, and the decrease in renal function was inhibited. The kidneys of rats treated from days -2 to 14 with antibodies to ICAM-1 and LFA-1 showed bright linear staining for rat IgG along the GBM, which did not differ in intensity from that seen in untreated rats. Furthermore, the titers of anti-GBM antibodies at 2 wk in treated rats were not lower than that seen in most of the untreated rats. There was, however, moderate reduction of anti-GBM antibodies at 5 wk in the treated rats.(ABSTRACT TRUNCATED AT 400 WORDS)     

Myocardial structural changes in long-term human severe sepsis/septic shock may be responsible for cardiac dysfunction

The present investigation sought to determine the cellular mechanisms directly dependent on long-term severe sepsis/septic shock that could lead to myocardial structural changes in humans. Human hearts from eight cases of long-term severe sepsis/septic shock arising from infection, as defined by the ACCP/SCCM Consensus Conference; eight cases of acute necrotizing pancreatitis and acute lung injury, a noninfectious pathologic cause of systemic inflammatory response; and three cases of accidental death without thoracic injury selected from autopsies were studied. Transmural blocks of myocardial tissue were excised from the middle portion of the left ventricular free wall and were fixed in formalin or were frozen. Histochemical and immunohistochemical methods were used to evaluate the cross-striations of the myocardial cells, the number and size of interstitial macrophages, the intracardiomyocyte accumulation of lipid, the actin/myosin contractile apparatus, and the expression of iNOS, nitrotyrosine, and TNF-alpha in the myocardia of septic and control hearts. Greater interstitial cellular infiltration composed of larger and elongated macrophages and TNF-alpha protein expression in myofibers, interstitial macrophage cell types, and smooth muscle cells and endothelial cell in the vessels; intracardiomyocyte lipid accumulation; scattered foci of actin/myosin contractile apparatus disruption; and increased expression for iNOS and nitrotyrosine in myocytes and interstitial macrophage cell types could be observed in long-term human septic myocardium as compared with normal and acute pancreatitis control myocardia. These findings give support to an opinion that structural changes could be responsible for long-term sepsis-induced myocardial dysfunction. The higher number of macrophages, most of them with morphological features of "activation," and TNF-alpha protein expression could favor the reduction of cardiac function in septic hearts. The intramyocyte lipid accumulation in these hearts very likely reflects myocardium ventricular contractile dysfunction. In addition, the increased expression of iNOS and the evidence for the significant presence of peroxynitrite in cardiomyocytes and interstitial macrophage cell types suggest that oxidative damage may play a role in actin/myosin disruption in the hearts of septic patients.