Effect of cyclosporin A on the biliary excretion of cholephilic compounds in rats.

Cyclosporin A (CsA) is known to cause cholestasis. CsA is reported to competitively inhibit the transport of the substrates of the bile salt export pump (Bsep), multidrug resistance protein 2 (Mrp2) and P-glycoprotein (P-gp) in the canalicular membrane vesicles. However, the inhibitory effect of CsA on various substrates of the canalicular ATP-dependent transporters in vivo is unknown. Therefore, in the present study, the acute effect of CsA on the biliary excretion of the substrates of Bsep, Mrp2 and P-gp was examined under the same condition. Ten minutes after the intravenous administration of CsA (25mg/kg), the biliary excretion of various bile acids and organic anions and cations was studied. CsA decreased the biliary excretion of tracer amounts of taurocholate, leukotriene C(4), estradiol-17beta-glucuronide, pravastatin, vinblastine and erythromycin. In contrast, the biliary excretion of high doses of taurocholate and sulfobromophthalein was only slightly or not inhibited by CsA. In conclusion, CsA may competitively inhibit biliary excretion of substrates of Bsep, Mrp2 and P-gp also in vivo, and CsA is considered to inhibit bile acid-dependent bile flow by the competitive inhibition of the canalicular transport of bile acids by Bsep.     

Expression and function of renal and hepatic organic anion transporters in extrahepatic cholestasis

Obstructive jaundice occurs in patients suffering from cholelithiasis and from neoplasms affecting the pancreas and the common bile duct. The absorption, distribution and elimination of drugs are impaired during this pathology. Prolonged cholestasis may alter both liver and kidney function. Lactam antibiotics, diuretics, non-steroidal anti-inflammatory drugs, several antiviral drugs as well as endogenous compounds are classified as organic anions. The hepatic and renal organic anion transport pathways play a key role in the pharmacokinetics of these compounds. It has been demonstrated that acute extrahepatic cholestasis is associated with increased renal elimination of organic anions. The present work describes the molecular mechanisms involved in the regulation of the expression and function of the renal and hepatic organic anion transporters in extrahepatic cholestasis, such as multidrug resistance-associated protein 2, organic anion transporting polypeptide 1, organic anion transporter 3, bilitranslocase, bromosulfophthalein/bilirubin binding protein, organic anion transporter 1 and sodium dependent bile salt transporter. The modulation in the expression of renal organic anion transporters constitutes a compensatory mechanism to overcome the hepatic dysfunction in the elimination of organic anions.     

急性胆道梗阻大鼠肝脏iNOS的表达及意义

目的 探讨大鼠阻塞性黄疸时诱导型一氧化氮合酶（iNOS）在肝脏中的变化及其意义.方法 选择成年SD大鼠60只,随机分为假手术对照组（S组）30只和阻塞性黄疸组（OJ组）30只.各组分别于术后1、3、7、10、14 d时点处死大鼠6只,检测血清丙氨酸氨基转移酶（ALT）、谷草转氨酶（AST）、血清总胆红素（TB）;观察肝组织普通病理改变以及iNOS蛋白、iNOS mRNA的表达情况.结果 S组肝细胞无肿胀、坏死,肝细胞索排列整齐.OJ组大鼠肝组织可见炎性细胞浸润,细小胆管和无管腔的小胆管增生,纤维组织细胞增生,肝细胞出现变性坏死.OJ组术后ALT、AST、TB迅速增高,与S组比较差异有统计学意义（P均＜0.05）.OJ组术后iNOS基因和蛋白水平表达升高,于第14天达到峰值,与S组比较差异有统计学意义（P均＜0.05）.结论 NO在阻塞性黄疸肝损害中具有双重作用.OJ早期NO可扩张血管,改善肝脏功能;随着iNOS增加,过量的NO产生细胞毒性可损伤肝脏.     

Expression of rat renal cortical OAT1 and OAT3 in response to acute biliary obstruction

Renal function in the course of obstructive jaundice has been the subject of great interest; however, little is known about the expression of renal organic anion transporters. The objective of this work was to study, in rats with acute extrahepatic cholestasis, the cortical renal expression of the organic anion transporter 1 (OAT1) and the organic anion transporter 3 (OAT3), in association with the pharmacokinetics and renal excretion of furosemide (FS). Male Wistar rats underwent bile duct ligation (BDL rats). Pair-fed sham-operated rats served as controls. All studies were carried out 21 hours after surgery. Rats were anesthetized and the pharmacokinetic parameters of FS and the renal elimination of FS were determined. Afterwards, the kidneys were excised and processed for immunoblot (basolateral membrane and renal homogenates) or immunocytochemical (light microscopic and confocal immunofluorescence microscopic analysis) techniques. The systemic and renal clearance of FS as well as the excreted and secreted load of FS increased in BDL rats. In kidneys from BDL rats, immunoblotting showed a significant increase in the abundance of both OAT1 and OAT3 in homogenates from renal cortex. In basolateral membranes from kidney cortex of BDL rats, OATI abundance was also increased and OAT3 abundance was not modified. Immunocytochemical techniques confirmed these results. In conclusion, acute obstructive jaundice is associated with an upregulation of OAT1 and OAT3, which might explain, at least in part, the increased systemic and renal elimination of FS.     

Regulation of epithelial injury and bile duct obstruction by NLRP3, IL-1R1 in experimental biliary atresia

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选择性胆管外引流对梗阻性黄疸大鼠肝切除术后肝再生的影响

90%以上肝门部胆管癌合并有不同程度的梗阻性黄疸,且多为完全梗阻性.术前多采取经皮经肝胆管引流(PTBD)以降低胆红素水平.肝门胆管癌PTBD与其他引起梗阻性黄疸的疾病有所不同:技术上困难,需多支肝管引流;引流的肝叶有可能是切除的肝叶;导管并发症发病率高等.     

Effects of nicorandil on renal function and histopathology in rats with partial unilateral ureteral obstruction

To evaluate the effects of nicorandil in a rat kidney model of partial unilateral ureteral obstruction (PUUO). Thirty male rats were randomly divided into three groups as follows: (1) Group 1 (Sham-control), ureters of the rats were manipulated but not ligated; (2) Group 2 (PUUO-untreated), PUUO was performed with two-thirds of the left ureter embedded in the psoas muscle; and (3) Group 3 (PUUO-nicorandil treated). After PUUO was established, nicorandil (15 mg/kg/day) was administered by gastric lavage for 21 days to determine its effects on PUUO-induced histopathological-, functional-, and oxidative stress-induced changes. The serum levels of blood urea nitrogen and creatinine were reduced in Group 3. The level of urinary albumin and the ratio of urinary protein/creatinine were increased in the kidneys of Group 2 but decreased in Group 3. Malondialdehyde value was decreased in Group 3 compared with Group 2. Antioxidant enzyme activities (catalase, superoxide dismutase, and glutathione peroxidase) were decreased in Group 2. Nicorandil treatment caused an increase in these enzyme activities. In Group 3, leukocyte infiltration and tubular dilatation were significantly reduced. Other parameters, such as degeneration of tubular epithelium and fibrosis, also showed a marked improvement in Group 3. Expression of inducible nitric oxide synthase in Group 2 and expression of endothelial nitric oxide synthase in Group 3 were significantly elevated. Nicorandil can inhibit renal tubular damage and tubulointerstitial fibrosis by reducing the effects of oxidative stress after PUUO.     

肾脏损伤时有机阴离子转运子表达变化及其意义

有机阴离子转运子(OAT)在机体清除各种内、外源性有机阴离子的过程中发挥极其重要的作用.在肾脏,OAT参与排泄许多外源性有机阴离子,如药物、环境中的化学物质、生物毒素以及许多内源性有机阴离子包括多种尿毒症毒素等.近年研究发现,各种肾脏疾病条件下OAT表达发生变化,并由此而产生相应病理生理效应.本文讨论了OAT在近端肾小管上皮细胞的生物学特征、肾脏病变状态下的表达变化及其病理生理学意义.     

Differential leptin responses to acute and chronic biliary obstruction in rats

BACKGROUND/AIMS: Recently leptin, a protein released from adipocytes, has been identified as a potent circulating satiety factor. We therefore undertook this series of experiments to examine leptin's role in the anorexia associated with biliary obstruction. METHODS: Rats underwent either surgical bile duct resection (BDR) or sham resection (sham). Body weight, and food and water intake were measured during a baseline period and for 8 days after surgery. At 4, 8 and 16 h as well as on days 2, 4, 6, and 8 postsurgery, sham and BDR rats were sacrificed and sera collected for subsequent measurement of leptin hormone concentration by RIA. White adipose tissue was collected on days 2, 4, 6 and 8 for leptin mRNA determination by Northern blot. RESULTS: Obstructive cholestasis in BDR rats caused significant anorexia for up to 7 days post-surgery, whereas in sham rats, a significant decrease in food intake was only observed in the first 24-h period following surgery. In both sham and BDR rats, water intake was significantly decreased during the first 24-h period after surgery, but had recovered to baseline levels by day 2 in both groups. Fat pad mass corrected to body weight was not significantly different between the two experimental groups. Serum leptin levels were significantly increased 4 and 8 h after surgery, had normalized by 16 h post-surgery, and were then decreased in BDR rats on days 2, 4, 6 and 8 compared with controls. Leptin mRNA levels in epididymal fat pads were decreased by approximately 2-fold in BDR rats compared with sham rats on days 2, 4, 6 and 8. Furthermore, day 5 BDR and sham rats demonstrated similar anorectic responses to centrally administered leptin. CONCLUSIONS: Leptin production is significantly increased early after biliary obstruction but is reduced after prolonged biliary obstruction. Increased circulating leptin levels may contribute to the profound anorexia observed early after biliary obstruction but appear not to mediate the anorexia observed during more chronic biliary obstruction.     

前列腺素E1对糖尿病肾病大鼠肾脏细胞凋亡的影响

目的 观察前列腺素E1 (PGE1)对糖尿病肾病(DN)大鼠肾脏细胞凋亡的影响. 方法 雄性Wistar大鼠65只,单次腹腔注射链脲佐菌素(STZ)制备DN大鼠模型.将造模成功的46只大鼠随机分为4组,PGE1组12只:前列地尔注射液(凯时)10 μg/d,静脉推注,10 d;血管紧张素转换酶抑制剂(ACEI)组12只:盐酸贝那普利片(洛汀新)10 mg/d,灌胃,8w;联合用药组11只:给予PGE1和ACEI联合治疗,剂量及时间同上;肾病对照组11只:仅给予相同体积生理盐水;另设正常对照组10只,处理同肾病对照组.治疗8 w后处死所有动物并测定24 h尿微量白蛋白、血尿素和血肌酐;HE染色观察肾脏病理和原位末端转移酶标记法(TUNEL)法检测细胞凋亡. 结果 治疗后8w,ACE1组、PGE1组、联合用药组24 h尿白蛋白水平均低于肾病对照组[(374.6±54.1)μg,(570.0±72.5)μg,(253.1±28.9)μg 比(1123.4±106.2 )μg,P＜0.01或P＜0.05];血尿素[(9.3±2.6)mmol/L,(11.0±3.5)mmol/L.(8.4±2.2)mmol/L比(15.1±4.0)mmol/L]和血肌酐[(74.5±19.2)μmol/L,(83.5±15.8) μmol/L,(64.6±17.3)μ mol/L比(117.7±33.0)μmol/L]水平均低于肾病对照组(P＜0.01或P＜0.05);与肾病对照组比较,各用药组肾脏组织病理改变减轻,联合用药组病理形态最佳.细胞凋亡在肾小球区域不明显.各组间差异无统计学意义(P＞0.05);除正常对照组外,各组肾小管细胞凋亡数显著多于肾小球. 结论 PGE1减少尿白蛋白的机制与肾小球细胞凋亡无明显相关,可能与肾小管细胞凋亡有关.     

Expression of the liver Na-independent organic anion transporting polypeptide (oatp-1) in rats with bile duct ligation

Background/Aims: In rats with cholestasis due to bile duct ligation, the expression of the Na⁺-dependent taurocholate co-transporting polypeptide, the major uptake system for conjugated bile acids in hepatocytes, is down-regulated. Our purpose was to examine the expression of the organic anion transporting polypeptide, a Na⁺-independent uptake system for bile acids and organic anions, in rats with bile duct ligation, and to compare the expression of organic anion transporting polypeptide to that of Na⁺-dependent taurocholate co-transporting polypeptide.Methods: Rats with bile duct ligation were studied after 1, 3 or 7 days. The expression of organic anion transporting polypeptide and Na⁺-dependent taurocholate co-transporting polypeptide proteins was examined by Western blot analysis and steady-state mRNA levels were determined by Northern blot analysis using cDNAs encoding organic anion transporting polypeptide and Na⁺-dependent taurocholate co-transporting polypeptide. Sham-operated animals were used as controls.Results: The expression of organic anion transporting polypeptide protein was slightly, but not significantly, decreased 1 day after ligation (10.3%); it was markedly decreased after 3 days (56.9%; p<0.03) and 7 days (45.8%; p<0.05) compared to sham-operated animals. Steady-state mRNA levels of organic anion transporting polypeptide was decreased by 79.7% (p<0.04), 48.8% (p<0.02) and 57.4% (p<0.02) after 1, 3 and 7 days respectively. For comparison, Na⁺-dependent taurocholate co-transporting polypeptide protein and mRNA levels were decreased by 73.8% (p<0.03) and 70.0% (p<0.05) at 1 day and remained low after 3 and 7 days.Conclusions: In rats with bile duct ligation, the expression of organic anion transporting polypeptide protein and mRNA is down-regulated. Down-regulation of organic anion transporting polypeptide seems less pronounced than that of Na⁺-dependent taurocholate co-transporting polypeptide. Nevertheless, it could contribute to a decreased uptake of potentially toxic bile acids or organic anions in this situation.     

单侧输尿管梗阻肾间质纤维化大鼠肾组织PHB1和 PHB2的表达及意义

目的：观察单侧输尿管梗阻（ UUO）肾间质纤维化（ RIF）大鼠肾组织PHB1和PHB2的表达,并探讨其意义。方法80只雄性6周龄Wistar大鼠随机分为模型组和假手术组各40只。模型组大鼠分离左侧输尿管后行双重结扎,假手术组只探查到肾包膜。于造模后第2周末和第4周末,每组各处死20只大鼠,取左侧肾组织进行肾脏病理学检查,并计算RIF指数;应用实时荧光定量PCR检测大鼠肾组织PHB1、PHB2、TGF-β1 mRNA;Western blot检测肾组织PHB1、PHB2、TGF-β1、Ⅳ型胶原（ Col-Ⅳ）和纤维连接蛋白（ FN）。结果与假手术组比较,模型组大鼠各时间点RIF指数增高,梗阻时间越长RIF指数越高,P均＜0．01;肾组织PHB1、PHB2 mRNA及蛋白表达均降低,梗阻时间越长表达水平越低,P均＜0．01;TGF-β1 mRNA及蛋白、Col-Ⅳ和FN蛋白表达均增高,P均＜0．01。肾组织PHB1蛋白表达与RIF指数、TGF-β1、Col-Ⅳ、FN呈负相关（ r分别为－0．86、－0．87、－0．70、－0．73,P均＜0．05）;PHB2蛋白表达与RIF指数、TGF-β1、Col-Ⅳ、FN呈负相关（r分别为－0．73、－0．81、－0．91、－0．84, P均＜0．05）;PHB1蛋白表达与PHB2蛋白表达呈正相关（ r＝0．78,P＜0．05）。结论在UUO所致RIF大鼠肾组织中,PHB1和PHB2表达显著降低,参与RIF的发生发展。     

原发性肝癌合并胆管梗阻的影像诊断与介入治疗

目的　探讨原发性肝癌合并胆管梗阻的影像诊断与介入治疗价值。方法　对 2 6例原发性肝癌合并胆管梗阻者进行回顾性分析 ,所有患者均行超声和CT检查 ,18例行MRI检查 ,11例行PTC检查 ,10例行ERCP检查 ,12例行胆道内支架置入术 ,2 2例经肝动脉化疗栓塞 (TACE)治疗。结果　 2 6例患者经超声、CT、MRI、PTC和ERCP等影像学检查后获得正确诊断。 12例患者分别置入了 4枚塑料内支架和 8枚金属支架 ,技术成功率为 10 0 % ,均有明显的减黄效果 ,患者术后 1周的血清胆红素水平由术前的 ( 2 96± 67) μmol/L降至 ( 10 4± 5 2 ) μmol/L(P <0 .0 5 )。 2 2例患者成功地进行了TACE治疗。结论　超声、CT、MRI和胆管造影检查对原发性肝癌合并胆管梗阻有较高的诊断价值 ,其相互补充有助于本病的正确诊断。胆道内支架置入术与TACE等介入治疗是其有效的治疗方法。     

一氧化氮在伴高脂血症急性出血坏死性胰腺炎大鼠胰腺及肾损害中的作用

目的:探讨一氧化氮(NO)含量变化对伴高脂血症急性出血坏死性胰腺炎(ANPl大鼠胰腺、肾损害的作用和对肾小球足细胞的影响.方法:♂SD大鼠30只,高脂饲料喂养4 wk建立大鼠高脂血症模型,将大鼠随机等分为3组;A组即高脂血症+ANP;B组即高脂血症+ANP+L-精氨酸(L-arg);C组即高脂血症+ANP+L-硝基精氨...     

脓毒症急性肺损伤大鼠肺组织AQP-1、AQP-5表达变化及意义

目的探讨脓毒症急性肺损伤大鼠肺组织水通道蛋白1（AQP-1）、AQP-5表达变化及意义。方法成年雄性SD大鼠60只,随机分为空白对照组、假手术组、模型组,每组20只。模型组采用盲肠结扎穿孔法复制脓毒症急性肺损伤模型,假手术组腹部探查取出盲肠后还纳腹腔,空白对照组不做手术处理。在造模后3、6、12、24h,每组各取出5只大鼠,处死后取肺组织,采用实时荧光定量PCR和Westernblot法检测肺组织AQP-1、AQP-5mRNA和蛋白。结果模型组造模后6h光镜下可见肺泡壁增厚、毛细血管充血、肺间质肺泡水肿、灶性出血,12h时上述改变最明显;空白对照组和假手术组肺组织无明显病理变化。模型组造模后6、12、24h时AQP1、AQP5mRNA及蛋白表达较同时点假手术组、空白对照组均降低（P均〈O．01）;iS模后6、12、24b时AQPl、AQP5mRNA及蛋白表达较同组3h均降低（P均〈0．01）。结论AQP．1、AQP．5表达降低在大鼠脓毒症急性肺损伤过程中可能发挥重要作用。     

Hyperbaric oxygenation promotes regeneration of biliary cells and improves cholestasis in rats

AIM:To investigate the effects of hyperbaric oxygenation(HBO) on regeneration of the biliary ductal system and postoperative cholestasis in hepatectomized rats.METHODS:HBO was performed in Wistar rats daily starting 12 h after a 70% partial hepatectomy.Regenerated liver weight,serum parameters and the proliferating cell nuclear antigen labeling index of hepatocytes and biliary ductal cells were measured.Hepatocyte growth factor(HGF),c-Met and transforming growth factor(TGF) β-1 mRNA expression levels were a...     

G3PD修饰蛋白对药物诱导的老年急性肾功能衰竭大鼠肾功能的影响

目的　探讨 3 磷酸甘油醛脱氢酶 (G3PD)的修饰蛋白 (MP)对庆大霉素诱导的老年急性肾功能衰竭 (ARF)大鼠肾小管修复以及肾功能改善的影响。　方法　将老年鼠及青年鼠各分成 3组 ,即正常组、模型组和MP组。庆大霉素腹腔注射 ( 14 0mg·kg-1 ·d-1 ) ,连续 7d ,制备大鼠ARF模型。采用镉还原比色法检测一氧化氮 (NO) ,采用硫代巴比妥酸法和羟胺法分别测定丙二醛 (MDA)和超氧化物歧化酶 (SOD) ,苦味酸法测定血肌酐 (Scr)。同时 ,光镜、电镜观察肾组织学改变。　结果　老年MP组与老年模型组相比 ,NO含量明显升高〔血清 ( 94 2 9± 7 68) μmol/L与 ( 70 14± 5 53 ) μmol/L ,肾脏( 5 94± 1 3 6) μmol/g组织与 ( 3 62± 1 11) μmol/g组织 ,均为P <0 0 1〕 ;青年MP组与青年模型组相比 ,NO同样明显升高。另外 ,老年、青年MP组与各自模型组相比 ,MDA降低 ,SOD升高 ,同时Scr下降 (均为P <0 0 1) ;光镜、电镜显示肾脏病理改变减轻。　结论　MP可以升高老年及青年ARF大鼠的NO含量 ,减轻肾脏病理变化 ,改善肾功能。     

急性冠状动脉综合征合并肾功能不全的支架术治疗

目的　评估急性冠状动脉 (冠脉 )综合征合并肾功能不全患者经皮腔内支架术的预后。方法　 6 3例急性冠脉综合征合并肾功能不全行冠脉内和或肾动脉支架植入术患者 (肾功能不全组 ) ,随机选取同期 6 3例一般情况匹配 ,肾功能正常行介入治疗患者 (对照组 )。比较两组临床特征、血管造影、支架术及随访情况。结果　肾功能不全组患者血清肌酐水平显著增高 [(177± 31) μmol/L比(98± 2 1) μmol/L ,P <0 0 0 1]、左室射血分数减低 (0 4 5± 0 10比 0 5 0± 0 0 9,P <0 0 5 ) ,冠脉多支病变增多 (84 %比 6 5 % ,P <0 0 5 )且肾动脉狭窄发生率显著增高 (2 7%和 8% ,P <0 0 5 ) ,13例患者在冠脉支架术同时行肾动脉支架术 (比较对照组 2例 ,P <0 0 5 ) ;两组冠脉支架术手术成功率和术中并发症相似 ;随访表明 ,肾功能不全组严重心脏不良事件发生率较高 (13%和 8% ,P =0 38) ,平均血清肌酐水平较术前降低 (177± 31μmol/L和 14 7± 11μmol/L ,P <0 0 5 ) ,9例 (6 9% )肾动脉狭窄患者肾动脉支架术后血清肌酐恢复正常。结论　急性冠脉综合征合并肾功能不全患者冠脉支架术安全、有效 ,2 / 3接受肾动脉支架术患者术后血清肌酐恢复正常。     

北京部分城区老年人慢性肾功能不全患病率及病因初探

目的了解北京市城区老年人肾脏疾病及肾功能不全的患病情况。方法于１９９２年及１９９７年对北京市部分城区同一老年人群５６０６例的肾脏疾病及肾功能不全的患病率分别进行调查。结果１９９２年及１９９７年肾功能不全的患病率分别为２．３７％及２．１７％,终末期肾病的患病率分别为０．０９％、０．１３％。原发病因中以肾硬化症占首位,其次为糖尿病,以后依次为梗阻性肾病、间质性肾病、肾小球肾炎、多囊肾和其他。结论这是国内首次对老年人肾功能不全的病因及患病率的调查,表明肾脏疾病是城区老年人的常见疾病,早期检出、早期治疗具有重要性。     

连续性肾脏替代疗法在重症急性肾功能衰竭治疗中的应用

目的 回顾分析连续性肾脏替代疗法（ＣＲＲＴ）在重症急性肾功能衰竭（ＡＲＦ）治疗中的应用和影响预后的因素。方法 １９８６年５月至１９９９年１月用ＣＲＲＴ治疗重症ＡＲＦ患者１０１例,回顾性分析了患者临床特点、ＣＲＲＴ方法和预后。结果 １０１例患者中６０例（５９．４％）度过疾病的急性期（存活组）,４１例（４０．６％）在急性期死亡（死亡组）,对两组患者的临床统计学资料、肾功能衰竭的特点、疾病严重程度（ＡＰ