肾小管上皮细胞损伤促进肾纤维化的研究进展

肾小管是肾脏的主要组成部分。其中肾小管上皮细胞（TECs）在慢性肾脏病（CKD）进展中发挥重要作用。TECs对各种损伤有免疫应答,随后产生和释放生物活性分子,促进肾小管间质炎症及纤维化。TECs受到损伤后会转化为分泌表型细胞,随之产生和释放促炎介质,例如促炎因子、趋化因子、活性氧、C反应蛋白,加速炎性细胞的募集,最终使得肾小管间质发生炎症因子浸润。并且在严重或重复性损伤后,TECs会发生结构和表型的改变,并伴有促纤维化因子的表达和产生,例如生长因子、外泌体,并通过与肾素-血管紧张素系统、细胞信号通路活化部分上皮-间充质转化机制发生纤维化反应,最终导致肾纤维化。本文对此进行综述。     

呼吸系统毒理学研究进展

呼吸系统是工业和环境毒物重要的毒作用靶。刺激性毒物引起上呼吸道从纤毛暂时性功能失常至细胞坏死脱落等多种损害。急性和亚急性接触肺毒物引起肺泡Ⅰ型细胞的坏死脱落和内皮细胞的损伤,导致肺水肿。我们的研究结果提示,动物接触高浓度刺激性毒物可发生成人呼吸窘迫综合征(ARDS)。肺组织的严重损伤可引起纤维细胞增生及阻塞性细支气管肺泡炎。纤维化是慢性肺损伤最重要的组织反应之一。我校曾利用免疫组化法研究了博莱霉素诱发大鼠肺间质纤维化时肺细胞外间质,结果提示;在肺纤维化过程中V型胶原的检测可用于评估纤维化病变的预后。     

肾脏纤维化相关细胞因子和信号通路

<正>肾脏纤维化是导致各种肾损伤的病因,是引起慢性肾脏病病情进展成终末期肾衰竭的病理损伤过程。各类原发,继发致肾损伤病因引起的慢性肾脏病,如肾病综合征、慢性肾小球肾炎、糖尿病肾病、高血压肾病等,病情进展成终末期肾衰竭,其实质就是肾脏固有细胞在炎症反应损伤之后,发生了纤维化和硬化。慢性肾脏纤维化的主要病理特征就是细胞外基质的过度沉积。肾脏纤维化的发生发展涉及多种信号通路和细胞因子。对这些细胞因子和信号通路的了解有助于以     

VEGF、MCP-1、CTGF与糖尿病肾病关系的研究进展

血管内皮生长因子(VEGF)可刺激血管内皮细胞分裂、增殖,增加血管通透性,在糖尿病肾病(DN)中主要引起炎性反应,促进蛋白尿的形成。单核细胞趋化蛋白-1(MCP-1)主要趋化单核细胞和T淋巴细胞,使各种炎性细胞尤其是单核细胞向病变部位聚集。在DN中MCP-1除引起肾进行性损伤外,还促进肾的纤维化。结缔组织生长因子(CTGF)是致纤维化因子,可促进肾的纤维化和蛋白尿的形成。     

抗肝纤维化药物治疗研究进展

肝纤维化(HF)是各种致病原因引起细胞外基质(ECM)在肝内过多沉积的过程,它是大多数慢性肝病所共有的病理特征,是众多慢性肝病发生发展的必经阶段.研究业已证明,肝星状细胞(HSC)在肝纤维化的发生发展过程中发挥关键作用.在损伤因子作用下,HSC增殖、活化,产生细胞外基质(ECM),是肝纤维化发生的关键细胞、重要环节[1].进展性肝纤维化具有一定的可逆性,现就其治疗研究进展综述如下.     

肝纤维化基因治疗策略

肝纤维化是一切慢性肝病的共同病理基础,各种病因引起肝脏慢性损伤的病理过程不同,但不同病因所致肝纤维化发生的最终的共同途径是肝星状细胞（HSC）的激活,转化为肌成纤维细胞（MFB）,进而产生大量的细胞外基质（ECM）,ECM的大量沉积最终导致了肝纤维化。现代研究表明。肝纤维化在去除损伤因素后尚有逆转的可能。     

肝脏细胞自噬在肝纤维化中的作用研究进展

肝纤维化是由于各种致病因子引起的肝脏结缔组织的异常增生。肝星状细胞的活化被普遍认为肝纤维化的中心环节,在肝纤维化过程中,自噬在不同的肝脏细胞中发挥着不同作用。一方面,在肝巨噬细胞、肝内皮细胞和肝实质细胞中,自噬可影响肝细胞炎症损伤反应抑制肝纤维化的发生;另一方面,在肝星状细胞中,自噬可影响氧化应激、内质网应激和脂质代谢等促进肝纤维化的发生。本文对肝脏不同细胞自噬在肝纤维化中的作用进行综述,为开发延缓和逆转肝纤维化的药物提供更完善的理论基础。     

肝星状细胞与肝纤维化

肝纤维化 (liverfibrosis)是指肝脏慢性炎症或损伤导致肝脏内纤维结缔组织异常增生 ,是所有慢性肝病共有的病理改变 ,其共同特点是以胶原蛋白为主的细胞外基质 (extracellularmatrix ,ECM )各成分合成增多 ,降解相对不足 ,过多沉积在肝内引起肝纤维化 ,若进一步发展引起肝小叶改建、假小叶和结节形成 ,则进入肝硬化。Safadi等[1 ] 研究表明肝纤维化在去除损伤因素后尚有逆转的可能 ,大大地激发了人们对肝纤维化发病机制的研究。目前 ,学者们普遍认为肝星状细胞 (hepaticstellatecell,HSC)是肝脏合成ECM的主要细胞[2 ] 。因此 ,肝星状细…     

ARB减少尿蛋白防治慢性肾脏疾病

当今世界,慢性肾脏疾病（CKD）日益严重地危害人类健康。过去一直认为蛋白尿仅仅反映肾小球损伤,但近年来的研究表明,由肾小球滤过的蛋白质可引起肾小管上皮细胞的损伤,并与小管间质纤维化的发生和发展密切相关。因此蛋白尿不仅反映肾小球损伤．而且是一个独立的导致肾脏病变进展的主要因素．任何能够使蛋白尿减少的治疗干预都有利于减慢肾脏疾病的进展。     

自主神经系统与肝纤维化关系的研究进展

肝纤维化（Heptic fibrosis,HF）是各种致病原因引起肝脏受到慢性损伤时,细胞外基质（cxtra～cllular matrix,ECM）在肝内可逆性沉积的创伤愈合过程。包括胶原在内的各种基质蛋白合成与分泌增多,而降解相对不足,沉积在肝脏中引起纤维化,     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg.kg) or i.p. (50 mg.kg) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) l.h. kg in the male rat and 10.6 (95% CI: 7.5, 15.0) l.h. kg in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p 0.001) in plasma obtained from the male (8.8 2.0%) compared with the female rat (11.7 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg x kg(-1)) or i.p. (50 mg x kg(-1)) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) 1 x h(-1) x kg(-1) in the male rat and 10.6 (95% CI: 7.5, 15.0) 1 x h(-1) x kg(-1) in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was approximately 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p < 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p < 0.001) in plasma obtained from the male (8.8 +/- 2.0%) compared with the female rat (11.7 +/- 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Interindividual variability in metabolic activation in humans in vivo

In assessing interindividual variability in metabolic activation, the toxic metabolite is often too unstable for conventional analysis. Possible alternatives include a stable product of the reactive metabolite e.g. cysteinyl derivatives of N-acetyl-4-benzoquinoneimine, the toxic metabolite of paracetamol, adducts with DNA or protein, and indirect measurement of the activity of the enzyme(s) producing the active metabolite. An example of the last approach is the use of furafylline, a highly specific inhibitor of human CYP1A2, to determine the extent of the metabolic activation of the cooked food mutagens PhIP and MeIQx. The extent of inhibition, determined from levels of unchanged amine in urine, is an indirect measure of the activity of the activation pathway. Further refinement of this approach, allied to improved measures of the biological process of interest should prove of value in evaluating interindividual variability and its role in the risk assessment process.     

Theophylline kinetics in peripheral tissues in vivo in humans

Several biochemical and cellular effects have been described for methylxanthines under in vitro conditions. However, it is unknown, whether threshold concentrations required to exert these effects are attained in target tissues in vivo. We therefore employed the microdialysis technique for measuring theophylline concentrations in peripheral tissues under in vivo conditions.Following in vitro and in vivo calibration, microdialysis probes were inserted into the medial vastus muscle and into the periumbilical subcutaneous adipose layer of healthy volunteers. Following single oral dose administration of 300 mg or i.v. infusion of 240 mg theophylline, in vivo time courses of theophylline concentrations were monitored in tissues and plasma. Major pharmacokinetic parameters (c_max, t_max, AUC) were calculated for plasma and tissue time courses. The mean AUC_tissue /AUC_plasma-ratio was 0.56 (p.o.) and 0.55 (i.v.) for muscle and 0.55 (p.o.) and 0.72 (i.v.) for subcutaneous adipose tissue.We conclude that microdialysis provides important information on the distribution and the tissue pharmacokinetics of theophylline.Abbreviations FPIA Fluorescence polarisation immuno assay - AUC Area under the curve - t_max Time to peak concentration - c_max Peak concentration     

休克时血中氧自由基的变化

本实验测定10名休克患者血浆和红细胞的丙二醛(MDA)、血浆总抗的氧化活性(AOA)的含量。结果表明:休克病人红细胞膜和血浆 MDA 含量(4.298±0.722;5.348±0.834)与对照组(3.235±0.682;4.356±1.081)比较明显增高(P<0.05);血浆 AOA(39.65±7.858)与对照组(48.21±10.81)比较明显降低(P<0.01)。提示:休克时,患者机体内自由基反应增强是引起组织细胞损伤的原因之一。     

Changes in angiopoietin expression in glomeruli involved in glomerulosclerosis in rats with daunorubicin-induced nephrosis

AIM: To study the potential pathological role of endogenous angiopoietins in daunorubicin-induced progressive glomerulosclerosis in rats. METHODS: Seventy male Wistar rats were allocated randomly into a daunorubicin group (DRB; n=40) or a control group (n=30). The rats in the DRB group were injected with DRB (15 mg/kg), in their tails. Subsequently, at intervals of 1, 2, 4, 6, 8, and 12 weeks, 5 male Wistar rats in each group were chosen randomly for 24 h urinary protein quantitative measurements (24 h UPQM), and determination of plasma tumor necrosis factor alpha (TNF-alpha), angiopoietin-1 (Ang1), and angiopoietin-2 (Ang2) levels. Kidney sections were examined by electron microscopy, Periodic Acid Schiff (PAS) staining, immunohistochemical staining and in situ hybridization histochemistry. RESULTS: As glomerulosclerosis progressed in the DRB group, expression of Ang1 mRNA and protein in glomeruli decreased and expression of TNF-alpha protein, Ang2 mRNA and protein in glomeruli increased. Expression of Ang1 mRNA and protein in glomeruli were negatively correlated with 24 h UPQM, Fn protein expression, and mean area of extracellular matrix (MAECM). In comparison, expression of Ang2 mRNA and protein in glomeruli were positively correlated with 24 h UPQM, Fn protein expression and MAECM; furthermore, there was a positive correlation between plasma Ang2 and 24 h UPQM. Plasma TNF-alpha and expression of TNF-alpha in glomeruli were positively correlated with expression of Ang2 mRNA and protein in glomeruli. There was a negative correlation between Ang1 protein expression and Ang2 protein expression in glomeruli. CONCLUSION: During DRB-induced glomerulosclerosis, podocyte injury led to a shift in the balance of Ang1 and Ang2 in glomeruli. Increased TNF-alpha in plasma and glomeruli may upregulate Ang2 expression in glomeruli. Elevated Ang2 in both plasma and glomeruli may mediate protein permeability through the glomerular filtration barrier. Moreover, local expression of Ang2 may facilitate the progress of glomerulosclerosis by upregulating a component expression of extracellular matrix.     

Trichinellosis in immigrants in Switzerland

We describe a case of trichinellosis diagnosed at the Division of Infectious Diseases, Hospital of Lugano, in January 2009. This case was associated with a cluster of cases and was traced to the consumption of contaminated meat after a wild boar hunt in Bosnia.