非肾脏来源的成体干细胞移植治疗肾脏疾病的进展

该文将着重探讨非肾脏来源的成体干细胞移植在治疗肾脏疾病中的研究进展.尽管骨髓造血干细胞(hematopietic stem cell,HSC)移植治疗肾脏疾病的机制存在争议,但是研究表明骨髓HSC能促进肾脏缺血再灌注损伤、IgA肾病和狼疮性肾炎等肾脏疾病的修复.间充质干细胞能归巢到受损肾脏,并通过旁分泌/自分泌机制,分泌细胞因子和释放微泡,发挥激活肾内细胞、促进血管生成、抑制氧化应激、抗凋亡、抗炎和抗纤维化等效应.成纤维细胞、系膜细胞、肾小管上皮细胞和尿液上皮细胞均可重编程为诱导多能干细胞,并通过诱导分化成特定类型的肾脏细胞.诱导肾脏疾病特异的多能干细胞为解决肾脏移植中肾源不足和治疗肾脏疾病(如糖尿病肾病和常染色体显性遗传性多囊肾病等遗传性肾脏疾病),提供了新的方法.     

肾脏缺血再灌注损伤的免疫学机制研究进展

固有免疫和适应性免疫参与肾脏缺血再灌注损伤(ischemia-reperfusion injury,IRI).在IRI急性期,肾血管内皮细胞黏附分子表达和血管通透性增加;肾小管上皮细胞补体C3沉积和Toll样受体2、4表达增加;树突状细胞早期活化导致中性粒细胞、巨噬细胞、自然杀伤细胞、CD4+T细胞和B细胞等迁移到缺血后肾脏.可溶性免疫分子(如补体活化产物、细胞因子和趋化因子)参与肾脏IRI急性损伤和(或)修复.Foxp3+调节性T细胞和旁路活化的巨噬细胞参与肾脏IRI修复;而B细胞限制IRI修复.     

β抑制蛋白2及微管相关蛋白轻链3在大鼠肾脏缺血再灌注损伤中的改变及意义

目的 探讨β抑制蛋白2(β-arrestin2)及微管相关蛋白轻链3(microtubule-associated protein light chain 3,LC3)在急性肾脏缺血再灌注损伤中的表达及与肾脏损害程度的相关性.方法 选用生后3~4周的雄性SD大鼠,随机分为正常组、假手术组、急性缺血再灌注损伤组.通过右侧肾脏切除,无创动脉夹夹闭左侧肾动脉45 min之后松开动脉夹,恢复肾脏血流,建立肾脏急性缺血再灌注损伤模型.并在恢复肾脏血流后12、24、36、48、72、96 h取肾脏及血液样本.采用免疫组织化学方法及West-ern blot方法检测各组肾组织中β-arrestin2及LC3蛋白的表达水平,检测各组的肾功能,并对各组肾脏病理学进行评分.结果 与正常组及假手术组相比,缺血再灌注损伤组血肌酐及肾脏病理学评分均有显著升高,其中肾脏损伤程度以缺血再灌注损伤后24 h最为明显;β-arrestin2及LC3蛋白在正常组及假手术组肾脏中的表达较少,在缺血再灌注损伤后的肾脏中表达显著升高,其中以缺血再灌注损伤后12 h时表达上调最为显著;β-arrestin2及LC3的表达改变先于肾脏病理改变,并且与肾脏损害程度呈正相关(r=0.821,P<0.05;r=0.913,P<0.05).结论 在肾脏急性缺血再灌注损伤时,β-arrestin2可能作为一个上游调控蛋白,通过对自噬的调节参与急性肾损伤的病理过程.     

肠缺血再灌注损伤的病理机制研究进展

正肠缺血再灌注(ischemia-Reperfusion,I/R)损伤是急性肠梗阻、创伤、休克、肠套叠、急性肠系膜动脉栓塞等常见疾病重要的病理生理过程,其病理机制复杂,包括炎症、凋亡、坏死等。在缺血时,细胞代谢障碍及组织结构发生损害。但是重新恢复血液灌注时,会加重缺血的组织细胞损伤。根据缺血再灌注损伤的相关机制,诸多实验已经进行有效肠I/R损伤的治疗,减轻肠道损伤~([1,2])。缺血再灌注引发局部及全身多系统发生重要病理生理改变,主要由于细胞毒素物质的释放、中性粒细胞和内皮细胞     

二氧化碳气腹致大鼠肾脏缺血再灌注损伤及异丙酚诱导核因子 E2相关因子表达的保护作用

目的：探讨二氧化碳气腹后致大鼠肾脏缺血再灌注损伤,以及异丙酚在缺血再灌注损伤过程中的保护作用机制。方法成年雄性 Wistar 大鼠48只,体重280~320 g,实验前12 h 禁食,自由饮水,采用随机数字表法将大鼠随机分为对照组、缺血组及再灌注组和异丙酚组,每组12只。对照组未经任何处理,仅经尾静脉泵注生理盐水1 h[10 ml /(kg.h)];缺血组在对照组的基础上,给予20 mmHg (1 mmHg =0.133 kPa)气腹压力1 h;再灌注组在缺血组的基础上,放开气腹压力后持续0.5 h;异丙酚组给予20 mmHg 气腹压力1 h,放开气腹压力后持续0.5 h,经尾静脉泵注异丙酚10 ml /(kg.h)(生理盐水10倍稀释)。观察各组尿素氮(blood urea nitrogen,BUN)、肌酐(creatinine,Cr)、超氧化物歧化酶(superoxide dismutase,SOD)、丙二醛(malondialdehyde,MDA)、核因子 E2相关因子(nuclear factor E2-related factor 2,Nrf2)表达的变化。结果对照组、缺血组、再灌注组的 BUN、Cr、MDA 水平逐渐增高,SOD 水平逐渐降低(P 均﹤0.05);与缺血组及再灌注组比较,异丙酚组的 BUN、Cr、MDA 水平明显降低,SOD 水平明显增高(P 均﹤0.05)。Nrf2蛋白及 mRNA 在对照组、缺血组、再灌注组、异丙酚组中的表达逐渐增加(P 均﹤0.05)。结论二氧化碳气腹对大鼠肾脏造成缺血再灌注损伤;异丙酚可通过调节 Nrf2蛋白的表达,对大鼠肾脏缺血再灌注损伤产生保护作用。     

缺血再灌注大鼠肾脏诱导型一氧化氮合酶表达的意义

目的观察缺血及缺血再灌注(IR)大鼠肾脏诱导型一氧化氮合酶(iNOS)表达变化的规律。方法制作大鼠肾脏缺血及IR模型,不同时间摘取肾脏,免疫组织化学法检测iNOS表达变化。HE染色观察肾脏损伤程度。结果缺血时及IR后iNOS表达均明显增强(P<0.05),且随时间呈一定的变化规律,呈先升高后下降趋势,24 h达峰值,72 h时降至2 h水平。结论肾脏缺血早期iNOS即起损伤作用,并于再灌注后加重损伤。     

脓毒症急性肾损伤发病机制的研究进展

脓毒症急性肾损伤是脓毒症多器官功能障碍的表现之一.当出现急性肾损伤时,往往提示病情危重.脓毒症急性肾损伤主要与肾脏血流动力学改变、缺血再灌注损伤、直接的炎症损伤、凝血和血管内皮细胞功能紊乱及细胞凋亡等有关.     

铁介导的氧自由基与缺血/再灌注损伤

缺血后重新恢复血流灌注是治疗缺血性疾病的有效手段之一。虽然缺血时可出现明显的组织病理改变,但是恢复血流灌注又可产生新的组织损伤,这就是缺血／再灌注损伤。缺血／再灌注损伤的发生机制尚未完全阐明,但是氧自由基对组织的氧化损伤是重要的发生机制之一。本文综述了缺血／再灌注时氧自由基的产生、转变与铁的关系,以及非蛋白结合铁在缺血／再灌注损伤中的作用。氧自由墓的产生、转变自由基（freeradical）是指含有一个或多个不成对电子的原子、原子团或分子。由氧诱发的自由基称为氧自由基（oxygenfreeradical,OFR）,如超氧阴…     

中期因子在肾脏疾病中的研究进展

中期因子作为一种肝素结合生长因子,主要作用于神经系统、癌症以及炎症反应,参与多种自身免疫炎症性疾病的发生、发展。该文就中期因子在肾脏缺血-再灌注损伤、新月体型肾小球肾炎、狼疮性肾炎、毛细血管内增生性肾小球肾炎和紫癜性肾炎等肾脏疾病中的作用进行综述。     

HSP70在缺血再灌注大鼠肾脏中的表达及意义

目的观察大鼠肾脏缺血及缺血再灌注(I/R)诱导热休克蛋白70(HSP70)的表达及意义。方法制作大鼠肾脏缺血及I/R模型,缺血组于缺血5、15和30min,I/R组于再灌注2、5、8、24、48、72h不同时间摘取肾脏,采用免疫组化方法检测肾脏HSP70的表达,同时采用HE染色,观察肾脏病理改变。结果在缺血组各时间点肾脏HSP70的表达无明显差异(P>0·05);肾脏I/R后,随时间延长,HSP70表达明显增强(P<0·05);肾脏病理显示,缺血时肾组织呈现局灶性及弥散性血管周围水肿,I/R后随时间延长肾脏损伤加重,损伤部位主要在肾小管,表现为空泡样变、小管萎缩、上皮细胞脱落及肾小球囊腔扩张等。结论HSP70在I/R后表达增强,但肾脏仍损伤严重,提示HSP70在肾脏I/R过程中没有起到主要的保护作用。     

干细胞移植在肾脏疾病中的应用

该文总结干细胞移植在肾脏损伤修复中的治疗证据,着重讨论干细胞种类的选择、移植方法的选择、干细胞抵达肾脏的可能机制和它起效的可能机制。脐带间充质干细胞的应用具有广阔的前景,但细胞移植的途径和最佳剂量仍有待进一步研究。干细胞抵达肾脏的机制可能和靶部位表达和释放趋化干细胞的因子有关,而干细胞的旁分泌和内分泌功能可能是它发挥作用的主要的机制。关于干细胞移植治疗肾脏疾病还有许多问题有待解决,但是干细胞移植仍是急慢性肾脏疾病的治疗中一个充满前景和希望的治疗策略。     

间充质干细胞对急性肺损伤作用机制的研究进展

间充质干细胞（mesenchymal stem cells,MSCs）作为一类来源广泛的低免疫原性多能干细胞已被用于多种危重症疾病及免疫性疾病的细胞治疗研究.大量临床研究显示,MSCs尽管在受损组织中的定植率低,但可以通过旁分泌因子来调节机体免疫、抑制炎症反应、修复受损上皮.儿童急性肺损伤（acute lung injury,ALI）是严重器官功能障碍时发生最早的并发症,目前尚无有效的药物治疗,病死率高.研究显示MSCs可以有效减轻肺水肿、改善肺功能,降低病死率,对于其作用机制的了解有利于推动MSCs从实验阶段转化为临床应用.本文将重点对MSCs修复ALI的相关机制进行综述.     

间充质干细胞治疗难治性肺疾病研究进展

难治性肺疾病是严重威胁患者健康的呼吸系统疾病,可导致肺功能受损甚至呼吸衰竭,目前常规的药物治疗效果欠佳,因此,寻找更有效的治疗方案尤为重要。间充质干细胞(MSCs)是一类多功能干细胞,可通过调节炎症和免疫反应,促进受损细胞修复以及通过旁分泌促进受损组织的再生,有望为难治性肺疾病的治疗提供新的治疗手段。     

输尿管梗阻大鼠肾脏肝细胞生长因子基因修饰的骨髓间充质干细胞移植

目的 观察携带肝细胞生长因子(HGF)基因的大鼠骨髓间充质干细胞静脉移植是否能够迁移、分布到单侧输尿管梗阻大鼠肾脏.方法 体外分离培养雄性大鼠骨髓间充质干细胞,并转染腺病毒-HGF (Ad-HGF),采用ELISA方法检测转染后HGF的表达情况;建立16只雌性单侧输尿管梗阻大鼠动物模型,随机分为移植组和对照组,移植组经鼠尾静脉注入Ad-HGF转染的骨髓间充质干细胞,对照组注入等量生理盐水,于术后7 d、14d取双侧肾脏,制作石蜡切片,Y染色体原位杂交方法检测雌性受体大鼠.肾脏中是否有骨髓间充质干细胞分布及分布情况.结果 移植组术后7 d梗阻侧肾脏可见Y染色体性别决定基因(Sty)阳性细胞,14d Sry阳性细胞数明显减少(P<0.05),主要分布在肾小管上皮细胞区,肾小球区未见Sry阳性细胞,而梗阻对侧及对照组双侧肾脏未见Sry阳性细胞.结论 鼠尾静脉移植携带HGF基因的骨髓间充质干细胞能够定居于输尿管梗阻侧肾脏,并分布到肾小管上皮细胞区.     

白细胞介素-4、-10对大鼠肾缺血再灌注损伤细胞凋亡的抑制作用

目的探讨白细胞介素-4(IL-4)和(或)IL-10对大鼠肾缺血再灌注损伤(IRI)是否有抑制细胞凋亡的作用及其机制。方法雌性SD大鼠30只随机分为5组(n=6):假手术组;手术 9g/L盐水对照组(NaCl组);手术 IL-4组(IL-4组);手术 IL-10组(IL-10组);手术 IL-4 IL-10组(IL-4 IL-10组)。用无损伤动脉夹钳夹大鼠双侧肾蒂45min制成肾IRI,钳夹松开时,各组迅速注射相应的IL或9g/L盐水,12h后取血及摘除左肾做病理切片。观察肾脏上皮细胞凋亡数(TUNEL法)。结果IL-4组肾脏上皮细胞凋亡水平无降低。IL-10组肾脏上皮细胞凋亡减轻。而联合运用IL-4 IL-10明显抑制大鼠肾脏上皮细胞凋亡。结论联合运用IL-4 IL-10明显抑制大鼠肾脏上皮细胞凋亡,对肾脏上皮细胞结构及功能有保护作用。     

Increased expression of fibroblast growth factors in segmental renal dysplasia

 Renal dysplasia (RD) is a disorganized development of renal parenchyma that results in a deficit of functional renal tissue. Dysplastic renal tissue is characterized by primitive tubular epithelium associated with increased mesenchyme. Several polypeptide growth factors (GF), which interact with target cells through a cell-surface membrane receptor, have been reported to be involved in the regulation of urothelial cell growth in normal and neoplastic states. Recent reports have demonstrated that basic fibroblast GF (bFGF, FGF-2) is a mitogen for renal proximal-tubule epithelial cells. Keratinocyte GF (KGF, FGF-7), which belongs to the FGF family, is believed to be a paracrine mediator of epithelial-cell proliferation. The aim of this study was to investigate the immunoactivity of bFGF and KGF and their receptors in the dysplastic kidney in order to further understand the pathogenesis of RD. Specimens of dysplastic upper poles of duplex kidneys were surgically resected from ten patients. Age-matched control material included six kidney specimens taken at autopsy from patients without evidence of urologic disease. Indirect immunohistochemistry was performed using the Strept-ABC method with four antibodies: bFGF, KGF, FGF receptor (flg), and KGF receptor (bek). There was absent or weak bFGF, KGF, flg, and bek immunoreactivity in normal kidneys. In the dysplastic kidneys, there was strong immunoreactivity of bFGF and KGF and their receptors in the epithelium of primitive tubules. Increased local expression of bFGF and KGF and their receptors in primitive tubules suggests that bFGF and KGF may play an important role in the development of RD.     

Protection against hyperoxia‐induced lung fibrosis by KGF‐induced MSCs mobilization in neonatal rats

MSCs have been shown to improve functional and pathological outcome in lung fibrosis. However, low in vivo cell engraftment of the transplanted cells limits their overall effectiveness. KGF (also known as FGF‐7) is a critical mediator of pulmonary epithelial repair through stimulation of epithelial cell proliferation. However, the role of KGF in MSCs and its therapeutic effects have not been identified. In this study, we investigated the effect of KGF on MSCs and its preventive role in hyperoxia‐induced fibrosis in neonatal rats. Neonatal rats exposed to normoxia or hyperoxia were randomly assigned to receive intraperitoneal injections of normal saline (PL), MSCs, or KGF pretreated MSCs on the fourth day of exposure. Our results showed that as compared to PL, while MSCs attenuated lung fibrosis, KGF pretreated MSCs exhibited enhanced preventive effect against lung fibrosis. This effect was partly attributed to enhanced mobilization of MSCs to the fibrotic lungs. In addition, the SHH signaling pathway, which is associated with the differentiation of stem cells was activated by KGF. Our data suggest that MSCs, especially KGF preconditioned MSCs, can attenuate lung fibrosis and KGF may regulate the MSCs behavior by activating SHH pathway.     

内毒素血症新生大鼠肾组织核因子κB和转化生长因子β1表达及超微结构的动态变化

目的 探讨新生大鼠内毒素血症时肾脏损伤与修复的可能机制.方法 将80只健康7日龄Wistar大鼠随机分为2组,每组40只,对照组腹腔内注射0.9%氯化钠溶液0.1 ml;内毒素组(LPS组)腹腔注射等容积LPS 5 mg/kg.每组大鼠分别于腹腔注射后1、4、8和12 h处死.采用免疫组织化学方法检测肾组织中核因子(NF)-κB及转化生长因子(TGF)-β1表达的动态变化,用透射电镜观察.肾组织超微结构变化.结果 NF-κB在对照组基本无表达,LPS组主要在肾小管上皮细胞表达,于实验后1 h即有升高,8 h达高峰,12 h略有下降.TGF-β1在对照组肾小管中少量表达,LPS组1、4及8 hTCF-β1表达较对照组差异无显著性,而12 h显著升高.电镜下观察到,LPS组于实验后4 h可见肾小球上皮细胞足突融合减少,肾小管上皮细胞线粒体空泡形成,刷状缘无明显改变;12 h肾小球上皮细胞足突明显融合,系膜细胞线粒体嵴断裂,肾小管上皮细胞线粒体扩张.结论 NF-κB参与了新生大鼠内毒素血症时肾损害的病理过程,而TGF-β1可能促进肾组织修复,同时可能抑制NF-κB产生.     

Renal Dysfunction is Common Among Adults After Palliation for Previous Tetralogy of Fallot

Long-term survival after tetralogy of Fallot (TOF) repair is excellent. However, little is published regarding late noncardiac complications. This study aimed to determine the prevalence and risk factors for renal dysfunction among adults after TOF repair. For this study, 56 adult patients with complete repair of TOF were identified, and their charts were retrospectively reviewed. An estimated glomerular filtration rate (eGFR) for each patient was calculated using the Modification of Diet in Renal Disease formula (MDRD). Using each patient’s eGFR, he or she was classified into stages based on the National Kidney Foundation chronic kidney disease (CKD) staging. Clinical parameters were compared among patients with and those without renal dysfunction to identify risk factors for renal impairment. The median estimated eGFR rate for the cohort was 78 ml/min/1.73 m². Based on the National Kidney Foundation CKD staging system, 54 % of the patients had at least stage 2 chronic renal disease. The risk factors identified were hypertension (p < 0.01), type 2 diabetes mellitus (p < 0.05), longer follow-up evaluation (p < 0.005), older age at complete repair (p < 0.05), and use of daily diuretics (p < 0.05). After repair of TOF, renal dysfunction is common at late follow-up evaluation. The study findings show the importance of routine assessment of renal function and the need to limit or avoid future episodes of acute kidney injury in this at-risk population.