Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6.

Cytokines are thought to be important mediators in physiologic and pathophysiologic processes affecting the central nervous system (CNS). To explore this hypothesis, transgenic mice were generated in which the cytokine interleukin 6 (IL-6), under the regulatory control of the glial fibrillary acidic protein gene promoter, was overexpressed in the CNS. A number of transgenic founder mice and their offspring exhibited a neurologic syndrome the severity of which correlated with the levels of cerebral IL-6 expression. Transgenic mice with high levels of IL-6 expression developed severe neurologic disease characterized by runting, tremor, ataxia, and seizure. Neuropathologic manifestations included neuro-degeneration, astrocytosis, angiogenesis, and induction of acute-phase-protein production. These findings indicate that cytokines such as IL-6 can have a direct pathogenic role in inflammatory, infectious, and neurodegenerative CNS diseases.     

Thioacetamide-induced hepatic fibrosis in transforming growth factor beta-1 transgenic mice

OBJECTIVE: Transforming growth factor beta-1 (TGF-beta 1) is thought to be one of the most important factors affecting the development of fibrotic processes in the liver. AIM: To discover whether endogenously higher TGF-beta 1 production influences the progression and reversibility of liver fibrosis in mice. METHOD: We compared thioacetamide-induced liver fibrosis between wild-type and transgenic mice overexpressing active TGF-beta 1 in the liver. Hepatic fibrosis was detected on histological sections, and fibrotic areas were measured by means of morphometric analysis. We also performed Northern blot hybridisation and gelatine zymography to improve our understanding of the process. RESULTS: The fibrotic process was faster in the transgenic animals, and regression after the withdrawal of the fibrogenic agent was slower. Fibrosis did not disappear completely from the TGF-beta 1 overexpressing mice, even at the endpoint of the experiment. CONCLUSION: Since the increased TGF-beta 1 production in the liver slowed down the regression of the liver fibrosis, the behaviour of these transgenic mice is more similar to the human situation, where cirrhosis is irreversible. We propose that this transgenic model is more suitable for investigating fibrotic liver diseases than the experiments done previously on wild-type rodents.     

Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis caused by overexpression of TGF-beta1

Studies on patients and large animal models suggest the importance of atrial fibrosis in the development of atrial fibrillation (AF). To investigate whether increased fibrosis is sufficient to produce a substrate for AF, we have studied cardiac electrophysiology (EP) and inducibility of atrial arrhythmias in MHC-TGFcys33ser transgenic mice (Tx), which have increased fibrosis in the atrium but not in the ventricles. In anesthetized mice, wild-type (Wt) and Tx did not show significant differences in surface ECG parameters. With transesophageal atrial pacing, no significant differences were observed in EP parameters, except for a significant decrease in corrected sinus node recovery time in Tx mice. Burst pacing induced AF in 14 of 29 Tx mice, whereas AF was not induced in Wt littermates (P<0.01). In Langendorff perfused hearts, atrial conduction was studied using a 16-electrode array. Epicardial conduction velocity was significantly decreased in the Tx RA compared with the Wt RA. In the Tx LA, conduction velocity was not significantly different from Wt, but conduction was more heterogeneous. Action potential characteristics recorded with intracellular microelectrodes did not reveal differences between Wt and Tx mice in either atrium. Thus, in this transgenic mouse model, selective atrial fibrosis is sufficient to increase AF inducibility.     

青蒿琥酯和双氢青蒿素对华支睾吸虫所致小鼠肝纤维化的治疗作用研究北大核心CSCD

目的观察和评估青蒿琥酯(ART)和双氢青蒿素(DHA)对华支睾吸虫所致小鼠肝纤维化的治疗作用。方法BALB/c小鼠35只,每只小鼠灌胃感染30个华支睾吸虫囊蚴,饲养30 d,建立小鼠华支睾吸虫病肝纤维化模型,随机分为7组,即青蒿琥酯组(ART组)、氯化钠组(NaCl组)、吡喹酮组(PZQ组)、吡喹酮+青蒿琥酯组[(PZQ+ART)组]、双氢青蒿素组(DHA组)、聚氧乙烯蓖麻油组(EL组)、吡喹酮+双氢青蒿素组[(PZQ+DHA)组],每组5只小鼠。采用腹腔注射法(ART)和经口灌胃法(DHA),用药剂量都为20 mg/kg,每天1次,连续用药30 d,合并PZQ用药组于感染华支睾吸虫囊蚴30 d后300 mg/kg PZQ连续灌胃治疗2次。取各组小鼠肝组织,应用苏木精-伊红(HE)和马松(Masson)染色显示小鼠肝组织病理学变化和胶原增生情况,应用荧光定量PCR和Western Blot检测肝组织α-SMA、TGF-β、Col I、Col III mRNA和蛋白表达,应用肝功检测试剂盒测定小鼠血清中丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)和碱性磷酸酶(ALP)含量。结果HE和Masson染色显示小鼠感染华支睾吸虫囊蚴30 d后肝脏汇管区有炎性细胞浸润,周围出现大量胶原纤维,有肝纤维化形成;Western Blot结果显示,感染组小鼠肝脏Col III表达量(1.26±0.01)高于未感染组(0.75±0.14)(t=2.01,P<0.05)。荧光定量PCR结果显示,接受ART和DHA治疗的小鼠与各自对照组相比,各纤维化相关基因mRNA表达水平没有显著差异。Western Blot结果显示,接受ART治疗后,ART组(0.32±0.04、0.81±0.09)和(PZQ+ART)组(0.16±0.01、1.02±0.18)的Col I、Col III蛋白表达水平都低于NaCl组(1.54±0.38、2.24±0.35),而且PZQ+ART组的Col I表达水平低于ART组(t=1.98,P<0.05);接受DHA治疗的小鼠α-SMA、Col I蛋白表达水平与对照组比较没有显著差异。肝功能检测结果显示,ART组(197.75±8.84)U/L和(PZQ+ART)组(234.66±42.54)U/L血清AST水平与NaCl组(150±20.29)U/L比较明显升高;(PZQ+DHA)组(29±12.98)U/L血清ALT水平较EL组(107.25±54.26)U/L和PZQ组(58±8.71)U/L降低,(PZQ+DHA)组(143±27.43)U/L血清AST水平较EL组(207±42.48)U/L降低(t=0.75,P<0.05)。结论青蒿琥酯(ART)在20 mg/kg剂量下对华支睾吸虫所致小鼠肝纤维化有治疗作用,合并杀虫抗纤维化效果更好,但对肝功有一定影响。双氢青蒿素(DHA)在20 mg/kg剂量下没有明显改善小鼠肝纤维化,但合并吡喹酮(PZQ)可以起到一定程度保肝作用。     

刀豆蛋白A诱导小鼠肝纤维化动物模型的建立

目的利用刀豆蛋白A建立昆明小鼠肝纤维化模型并探讨其机制。方法昆明小鼠210只,随机分为7组,正常A组(注射等量生理盐水),刀豆蛋白A10mg每周1～3次(分别为B、C、D组)、15mg每周1～2次(分别为E、F组)、20mg每周1次(G组),采用尾静脉注射法攻击昆明小鼠,分别在第1周、第5周、第12周和第20周处死3只小鼠,留取肝组织标本行苏木精-伊红染色、纤维Masson染色,并行Knodell HAI和Ishak肝纤维化半定量计分,最后一次留取血清标本,检测血清IL-18、TNF-α和IFN-γ。结果 15mg每周1次,10mg每周2次组实验早期肝脏组织以坏死为主;实验中期(5～12周)坏死减轻,细小纤维条索出现;实验晚期(20周)纤维间隔逐渐增宽。10mg每周1次组实验晚期(20周)纤维条索形成,纤维间隔有增宽趋势。10mg每周3次组和20mg每周1次组全部死亡前,未发现有明显的肝纤维化形成。肝组织炎症活动度半定量计分显示刀豆蛋白A注射次数和注射剂量较大组评分较高(P<0.05)。肝纤维化半定量计分显示10mg每周2次组较15mg每周1次,10mg每周1次组高(P<0.05)。各组注射刀豆蛋白A后均出现了IL-18、TNF-α和IFN-γ的升高,并且IL-18和TNF-α表现出相关性(r=0.889,P<0.05)。结论利用刀豆蛋白A建立昆明小鼠的肝纤维化模型,其形成机制与IL-18、TNF-α和IFN-γ的升高密切相关。     

Ectopic automaticity induced in ventricular myocytes by transgenic overexpression of HCN2

Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) are expressed in the ventricles of fetal hearts but are normally down-regulated as development progresses. In the hypertrophied heart, however, these channels are re-expressed and generate a hyperpolarization-activated, nonselective cation current (I_h), which evidence suggests may increase susceptibility to arrhythmia. To test this hypothesis, we generated and analyzed transgenic mice overexpressing HCN2 specifically in their hearts (HCN2-Tg). Under physiological conditions, HCN2-Tg mice exhibited no discernible abnormalities. After the application of isoproterenol (ISO), however, ECG recordings from HCN2-Tg mice showed intermittent atrioventricular dissociation followed by idioventricular rhythm. Consistent with this observation, 0.3 μmol/L ISO-induced spontaneous action potentials (SAPs) in 76% of HCN2-Tg ventricular myocytes. In the remaining 24%, ISO significantly depolarized the resting membrane potential (RMP), and the late repolarization phase of evoked action potentials (APs) was significantly longer than in WT myocytes. Analysis of membrane currents revealed that these differences are attributable to the I_h tail current. These findings suggest HCN2 channel activity reduces the repolarization reserve of the ventricular action potential and increases ectopic automaticity under pathological conditions such as excessive β-adrenergic stimulation.     

G蛋白激酶4γA142V转基因小鼠血压升高的机制探讨

目的探讨G蛋白激酶(GRK)4γ变异体A142V转基因小鼠血压升高的原因,以期了解GRK4γ在调控血压中的作用。方法以GRK4γA142V转基因小鼠为研究对象,分别对其血压、肾脏尿钠排泄功能、D1多巴胺受体的表达进行测定;并应用GRK4反义核苷酸技术处理HK-2细胞,研究在GRK4表达受到抑制的情况下D1受体的表达变化。结果与对照小鼠相比,GRK4γA142V转基因小鼠血压明显增高,肾脏D1受体介导的利尿、利钠作用明显下降,伴有肾脏皮质膜D1受体表达降低(0.6±0.2比1.5±0.2,n=3)、磷酸化程度增高[(65±7)DU比(35±7)DU,n=3];反义核苷酸抑制GRK4(1.2±0.1比1.3±0.1比0.6±0.1,n=6)表达后,D1受体的表达量增高(0.7±0.1比0.8±0.1比1.5±0.2,n=6),说明D1受体功能下降是GRK4γA142V转基因小鼠血压升高的原因。结论GRK4γ与高血压的发生关系密切,GRK4γA142V转基因小鼠血压升高与肾脏D1受体功能下降有关。     

湖北海棠叶总黄酮对日本血吸虫感染小鼠肝纤维化的抑制作用

目的探讨湖北海棠叶总黄酮对日本血吸虫感染所致小鼠肝纤维化的保护作用。方法随机将未感染和感染日本血吸虫尾蚴昆明小鼠分成A～F6组。即未感染空白对照组（A）、模型组（B）、复方鳖甲软肝片阳性组（C）、湖北海棠叶总黄酮治疗高剂量[114mg（/kgd）]组（D）、中剂量[57mg（/kgd）]组（E）、低剂量[28.5mg（/kgd）]组（F）,每组10只。感染后第42天,C、D、E、F组均用吡喹酮驱虫治疗,500mg/（kgd）2日疗法,之后各组开始灌胃给药持续治疗60d,A组和B组生理盐水灌胃对照。实验结束处死小鼠,留取肝脏组织和血清,测定血清中丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、透明质酸（HA）含量,计算肝体指数,测定肝组织中羟脯氨酸（HYP）。苏木素伊红和Masson胶原纤维染色观察小鼠肝组织变性、虫卵肉芽肿与胶原沉积等病理改变。结果与A组相比,B、C、D、E、F组小鼠肝脏有明显虫卵肉芽肿形成、胶原沉积与肝纤维化,伴有不同程度肝细胞炎性损伤坏死。血清中ALT、AST、HA和肝组织中HYP含量均明显升高（P〈0.05或P〈0.01）。与B组相比,湖北海棠叶总黄酮高、中、低剂量组ALT、AST、HA和HYP含量及肝体指数均明显降低（P〈0.05或P〈0.01）,肝组织坏死与胶原沉积明显减轻,虫卵肉芽肿面积减小。结论湖北海棠叶总黄酮具有抗血吸虫性肝纤维化作用。     

Rosiglitazone prevents murine hepatic fibrosis induced by Schistosoma japonicum

AIM： To evaluate the effect of rosiglitazone in a murine model of liver fibrosis induced by Schistosoma japonicum infection. METHODS： A total of 50 mice were randomly and averagely divided into groups A, B, C, D and E. The mice in group A served as normal controls, while those in the other four groups were infected with Schistosoma japonicum to induce the model of liver fibrosis. Besides, the mice in groups C, D and E were treated with praziquantel, rosiglitazone and praziquantel plus rosiglitazone, respectively. NF-κB binding activity and expression of PPARγ-mRNA were determined by Western blot assay and real-time quantitative PCR. Radioimmunonassay technique was used to detect the serum content changes of TNF-α and IL-6. Histological specimens were stained with HE. Expression of TGF-β1, a-smooth muscle actin and type Ⅰand type Ⅲ collagen was detected by immunohistochemistry and multimedia color pathographic analysis system.
RESULTS： Inflammation and fibrosis in the rosiglitazone plus praziquantel treatment group （group E） were lightest among the mice infected with Schistosoma （P 〈 0.05）. To further explore the mechanism of rosiglitazone action, we found that rosiglitazone can significantly increase the expression of PPARγ [E： -18.212 ± （-3.909） vs B： -27.315 ± （-6.348） and C： -25.647 ± （-5.694）, P 〈 0.05],reduce the NF-κB binding activity （E： 88.89 ± 19.34 vs B： 141.11 ± 15.37, C： 112.89 ± 20.17 and D： 108.89 ± 20.47, P 〈 0.05）, and lower the serum level of TNF-α （E： 1.613 ± 0.420 ng/mL vs B： 2.892 ± 0.587 ng/mL, C： 2.346 ± 0.371 ng/mL and D： 2.160 ± 0.395 ng/mL, P 〈 0.05） and IL-6 （E： 0.106 ± 0.021 ng/mL vs B： 0.140 ± 0.031 ng/mL and C： 0.137 ± 0.027 ng/mL, P 〈 0.05） in mice with liver fibrosis. Rosiglitazone can also substantially reduce the hepatic expression of TGF-β1, α-SMA type Ⅰand type Ⅲ collagen in mice with liver fibrosis. CONCLUSION： The activation of PPARγ by its ligand can retard liver fi     

Inclusion body myositis-like phenotype induced by transgenic overexpression of beta APP in skeletal muscle

Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, although affected muscle fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease. Accumulation of the amyloid-beta peptide, which is derived from proteolysis of the larger amyloid-beta precursor protein (betaAPP), seems to be an early pathological event in Alzheimer's disease and also in IBM, where in the latter, it predominantly occurs intracellularly within affected myofibers. To elucidate the possible role of betaAPP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which we selectively targeted betaAPP overexpression to skeletal muscle by using the muscle creatine kinase promoter. Here we report that older (>10 months) transgenic mice exhibit intracellular immunoreactivity to betaAPP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of betaAPP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results are consistent with a pathogenic role for betaAPP mismetabolism in human IBM.     

小鼠日本血吸虫性肝纤维化组织TGF-β1及Smads的表达

目的:探讨小鼠日本血吸虫病纤维化肝组织中转化生长因子(transforming growth factor-β1,TGF-β1)、Smad2/3、Smad4和Smad7的表达和肝纤维化的发病机制.方法:清洁级6-8 wk龄ICR小鼠80只,雌雄各半,随机分为模型组和正常对照组,用血吸虫尾蚴腹部贴附法制成动物模型,正常组未予处理.感染后wk 4、6、8和12末分批处死2组小鼠且称肝脾质量,取部分肝做病理学观察,HE染色和猩红染色,制作组织芯片,免疫组化检测TGF-β1、Smad2/3、Smad4和Smad7在各细的表达状况.结果:与正常组相比,模型组小鼠肝脾质量和肝指数均高(肝,12 wk:2.99±0.28 g vs 1.83±0.13 g;脾,12 wk:0.87±0.15 g vs 0.14±0.02g;肝指数,12 wk:0.09±0.01 vs 0.04±0.00;均P＜0.01),TGF-β1和Smad2/3表达也均高于正常对照组(TGF-β1.12 wk:0.105±0.008 vs 0.024±0.002;Smad2/3.12 wk:0.094±0.009 vs 0.003±0.001,均P＜0.01),以上指数分别与肝纤维化程度呈正相关(r=0.635,0.482,0.646,0.347,0.662;均P<0.01);Smad4表达高于对照组且随着纤维化的发展表达量在逐渐下降(4wk:0.075±0.011 vs 0.023±0.006.6 wk:0.043±0.008 vs 0.010±0.002.8 wk:0.038±0.009 vs 0.003±0.002.12 wk:0.028±0.004 vs 0.013±0.006;均P＜0.01).Smad7仅8 wk表达增强.结论:TGF-β1和Smad2/3表达增强在肝纤维化的发生中起重要作用,Smad4可能主要在纤维化的早中期发挥效应.     

Improved metabolic disorders of insulin receptor-deficient mice by transgenic overexpression of glucokinase in the liver

AIMS/HYPOTHESIS: Insulin receptor null mutant mice develop severe diabetes, ketoacidosis and liver steatosis and die within 1 week after birth. Since the liver plays an essential role in the control of glucose homeostasis, we examined in this work whether the metabolic disorders of insulin receptor-deficient mice could be improved upon restoration of hepatic glucose metabolism by transgenic constitutive overexpression of glucokinase selectively in the liver. METHODS: We first generated transgenic mice overexpressing rat glucokinase cDNA under control of the liver-specific phenylalanine hydroxylase gene promoter. These transgenic mice were crossed with heterozygous insulin-receptor-null mutants to produce homozygous insulin-receptor-null mice overexpressing glucokinase in the liver. RESULTS: The transgenic mice overexpressing glucokinase in the liver showed improved glucose tolerance and were mildly hypoglycaemic and hyperlipidaemic under starved conditions. The introduction of the glucokinase transgene in insulin receptor null mice did not prevent the development of glycosuria. However, ketoacidosis was delayed by more than 1 week and survival was prolonged to 10 to 16 days in 16% of the pups. In these longer surviving pups, serum glucose and triglyceride concentrations were lowered, hepatic glycogen stores were reconstituted and liver steatosis was absent as compared with the pups which had developed strong ketoacidosis and died earlier. CONCLUSIONS/INTERPRETATION: These results show that overexpression of hepatic glucokinase can compensate, in part, for the metabolic disorders developed by insulin receptor-deficient mice. This shows the importance of improving hepatic function in diabetes and must revive interest in enhancement of glucokinase activity as a therapeutic strategy for the treatment of diabetes.     

Melatonin ameliorates experimental hepatic fibrosis induced by carbon tetrachloride in rats

AIM： To investigate the protective effects of melatonin on carbon tetrachloride （CCl4）-induced hepatic fibrosis in experimental rats.
METHODS： All rats were randomly divided into normal control group, model control group treated with CCl4 for 12 wk, CCl4 ＋ NAC group treated with CCl4 ＋ NAC （100 mg/kg, i.p.） for 12 wk, CCl4 ＋ MEL-1 group treated with CCl4 ＋ melatonin （2.5 mg/kg） for 12 wk, CCl4 ＋ MEL-2 group treated with CCl4 ＋ melatonin （5.0 mg/kg） for 12 wk, and CCl4 ＋ MEL-3 group treated with CCl4 ＋ melatonin （10 mg/kg）. Rats in the treatment groups were injected subcutaneously with sterile CCl4 （3 mL/kg, body weight） in a ratio of 2：3 with olive oil twice a week. Rats in normal control group received hypodermic injection of olive oil at the same dose and frequency as those in treatment groups. At the end of experiment, rats in each group were anesthetized and sacrificed. Hematoxylin and eosin （HE） staining and Van Gieson staining were used to examine changes in liver pathology. Serum activities of alanine aminotransferase （ALT）, aspartate aminotransferase （AST） and protein concentration weremeasured with routine laboratory methods using an autoanalyzer. Hydroxyproline （HYP） content in liver and malondialdehyde （MDA） and glutathione peroxidase （GPx） levels in liver homogenates were assayed by spectrophotometry. Serum hyaluronic acid （HA）, laminin （LN）, and procollagen Ⅲ N-terminal peptide （PⅢNP） were determined by radioimmunoassay.
RESULTS： Pathologic grading showed that the fibrogenesis was much less severe in CCl4 ＋ MEL3 group than in model control group （u = 2.172, P 〈 0.05）, indicating that melatonin （10 mg/kg） can significantly ameliorate CCl4-induced hepatic fibrotic changes. The serum levels of ALT and AST were markedly lower in CCl4 ＋ MEL treatment groups （5, 10 mg/kg） than in model control group （ALT： 286.23 ± 121.91 U/L vs 201.15 ± 101.16 U/L and 178.67 ± 103.14 U/L, P = 0.028, P = 0.007; AST： 431.00 ± 166.35 U/L vs 321.23 ± 162.48 U/L and 292.42 ± 126.23 U/L, P = 0.043, P = 0.013）. Similarly, the serum laminin （LN） and hyaluronic acid （HA） levels and hydroxyproline （HYP） contents in liver were significantly lower in CCl4 ＋ MEL-3 group （10 mg/kg） than in model control group （LN： 45.89 ± 11.71 μg/L vs 55.26 ± 12.30 μg/L, P = 0.012; HA： 135.71±76.03 μg/L vs 201.10 ± 68.46 μg/L, P = 0.020; HYP： 0.42 ± 0.08 mg/g tissue vs 0.51 ± 0.07 mg/g tissue, P = 0.012）. Moreover, treatment with melatonin （5, 10 mg/kg） significantly reduced the MDA content and increased the GPx activity in liver homogenates compared with model control group （MDA： 7.89 ± 1.49 noml/mg prot vs 6.29 ±1.42 noml/mg prot and 6.25 ±2.27 noml/mg prot, respectively, P = 0.015, P = 0.015; GPx： 49.13 ±8.72 U/mg prot vs 57.38 ±7.65 U/mg prot and 61.39 ±13.15 U/mg prot, respectively, P = 0.035, P = 0.003）.
CONCLUSION： Melatonin can ameliorate CCl4 -induced hepatic fibrosis in rats. The protective effect of melatonin on hepatic fibrosis may be related to its antioxidant activities,     

吡菲尼酮对牛血清蛋白诱导的肝纤维化大鼠肝损害的保护作用观察

目的探讨吡菲尼酮对牛血清蛋白诱导的大鼠肝纤维化的影响。方法雄性Wistar大鼠30只被随机分为3组,给予模型组腹腔注射牛血清白蛋白,正常对照组接受等量的生理盐水腹腔注射,治疗组在腹腔注射牛血清白蛋白5 w后,按200 mg·kg-1·d-1灌胃给药吡菲尼酮,治疗4 w后处死试验动物,留取肝脏组织,行HE和Masson染色,观察肝脏病理学改变,采用免疫组化法检测Smad6蛋白表达。结果与模型组比,吡菲尼酮治疗组肝组织纤维化S3和S4期病变较模型组明显减少,炎症细胞浸润明显减少,胶原纤维间隔缩小,着色变浅;模型组肝组织Smad6相对表达量为(108.2±33.6),显著低于吡菲尼酮治疗组[(329.4±39.2),P0.05]。结论吡菲尼酮可抑制牛血清蛋白诱导的大鼠肝纤维化,其机制与通过上调Smad 6蛋白表达有关。     

Interleukin 6: insights to its function in skin by overexpression in transgenic mice.

Interleukin 6 (IL-6) is a cytokine that mediates a wide range of inflammatory and immune responses. Its expression is elevated in inflammatory or immunodeficient diseases, including psoriasis, rheumatoid arthritis, and AIDS. To explore the role of IL-6 in skin, we utilized a human keratin 14 (K14) promoter to express IL-6 in the basal cells of stratified squamous epithelia of transgenic mice. Mice expressing the K14-IL-6 transgene were smaller than normal and exhibited retarded hair growth. Surprisingly, IL-6 expression did not lead to enhanced epidermal proliferation, but it did result in a thicker stratum corneum, with an otherwise seemingly normal program of differentiation. IL-6 expression did not lead to leukocytic infiltration, making it unlikely that it has direct proinflammatory activity in skin. Based on this study, one role of IL-6 relevant to host defense may be to enhance the stratum corneum, thereby providing increased protection from injurious stimuli or infection. If IL-6 plays additional roles in the skin, it is likely to act synergistically with factors that IL-6 alone cannot induce.     

激动素抗大鼠肝纤维化的实验研究

目的:研究激动素对实验性肝纤维化的影响,探讨作用机制。方法:用CCl4诱导形成大鼠肝纤维化模型,使用0.1%激动素溶液0.5ml.100g-1.d-1,背部皮下注射,治疗12周,设正常对照组和模型组。血清ALT用全自动生化分析仪检测,血清透明质酸(HA)、层黏连蛋白(LN)、Ⅲ型前胶原(PCⅢ)和Ⅳ型胶原(CⅣ)含量用RIA方法检测。肝组织学检查:采用苏木精-伊红染色观察肝组织炎症和纤维化程度。结果:激动素组ALT水平与模型组ALT水平分别为(57.40±17.49)U/L和(84.70±31.85)U/L,两组比较差异有显著性意义(P<0.05)。激动素组LN和CⅣ含量分别为(29.25±6.67)ng/ml和(14.84±5.84)ng/ml,较模型组(37.18±10.06)ng/ml、(35.69±30.84)ng/ml明显降低(P<0.05);激动素组HA和PCⅢ含量分别为(136.25±76.83)ng/ml和(11.43±3.67)ng/ml,较模型组(168.55±56.19)ng/ml、(14.64±8.00)ng/ml有不同程度降低,但无统计学意义。组织学检测结果表明,模型组肝脏炎症和纤维化程度明显高于激动素组。结论:激动素对实验性大鼠肝纤维化具有抑制作用。     

Effects of RNA interference targeting transforming growth factor-beta 1 on immune hepatic fibrosis induced by Concanavalin A in mice

BACKGROUND:Previous studies have shown that transforming growth factor-beta 1(TGF-β1)is the most potent means of stimulating liver fibrogenesis by myofibroblast-like cells derived from hepatic stellate cells. Thus,TGF-β1 could be a target for treating hepatic fibrosis. This study aimed to investigate the inhibitory effects of specific TGF-β1 small interference RNA(siRNA)on immune hepatic fibrosis induced by Concanavalin A(Con A)in mice. METHODS:Three short hairpin RNAs targeting different positions of TGF-β...     

Phenotypic manifestations of insulin-like growth factor-binding protein-3 overexpression in transgenic mice

In cell culture systems insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) can both enhance and inhibit IGF-I action. To investigate the biological role of IGFBP-3 in vivo, transgenic (Tg) mice that constitutively overexpress the human IGFBP-3 complementary DNA (cDNA) driven by the mouse phosphoglycerate kinase I (PGK) and the cytomegalovirus (CMV) promoters were examined. Serum levels of human IGFBP-3 in CMVBP-3 and PGKBP-3 Tg mice were 4.7 and 5.8 microgram/ml, respectively and total IGFBP-3 was increased 4.9- and 7.7-fold compared with that in wild-type (Wt) mice. In PGKBP-3 Tg mice the levels of transgene expression were similar in all tissues. Although CMVBP-3 mice demonstrated similar levels of expression of the transgene as PGKBP-3 mice in most tissues, markedly elevated expression was apparent in the kidney and heart. The transgene-derived IGFBP-3 circulated as a 150-kDa ternary complex, and serum IGF-I levels were elevated 1.9- to 2.8-fold in Tg mice compared with Wt mice. A significant reduction in birth weight of approximately 10% and a modest reduction in litter size were apparent in both Tg strains. Early postnatal growth, as assessed by both body weight and length, was significantly reduced in Tg mice compared with Wt mice. This was more marked in PGKBP-3 than in CMVBP-3 mice, who demonstrated a propensity to adiposity after weaning. The relative organ weights of brain and kidney were reduced in both Tg strains, whereas liver size and epididymal fat were significantly increased in CMVBP-3, but not PGKBP-3, mice. Our data indicate that overexpression of IGFBP-3 is associated with modest intrauterine and postnatal growth retardation despite elevated circulating IGF-I levels.