不同剂量白藜芦醇对博莱霉素致大鼠肺纤维化的干预比较

目的 比较不同剂量的白藜芦醇对博莱霉素致大鼠肺纤维化的干预作用.方法 90只SD大鼠随机分成正常对照组、模型组、Res低剂量干预组、Res中剂量干预组、Res高剂量干预组、DXM干预组.博莱霉素(5 mg/kg)气管内灌注建立大鼠肺纤维化模型.各组均采用HE染色、Masson染色、HYP含量测定.观察不同剂量的白藜芦醇对大鼠肺纤维化的干预作用.结果 Res中、高剂量干预组及DXM干预组大鼠一般情况均较模型组好.HE染色、Masson染色显示Res低剂量干预组大鼠肺组织肺泡炎和肺纤维化程度较模型组没有显著差异(P均＞0.05).Res中、高剂量干预组及DXM干预组病理组织染色可见肺泡炎和肺纤维化程度在各时间点均明显轻于模型组(P＜0.05).HYP含量测定中Res低剂量干预组与模型组无显著性差异(P＞0.05),而Res中、高剂量干预组及DXM干预组各时间点HYP含量均低于模型组(P＜0.05).结论 不同剂量的白藜芦醇对博莱霉素致大鼠肺纤维化的干预作用不尽相同.中、高剂量白藜芦醇的干预作用基本同地塞米松的干预作用.     

不同剂量地塞米松对博莱霉素致大鼠肺纤维化的影响

目的观察不同剂量地塞米松（DXM）对博莱霉素致大鼠肺纤维化的治疗作用及其副作用,探索DXM治疗动物肺纤维化的有效安全剂量。方法144只健康雄性SD大鼠随机分为4组：对照组（n=18）、DXM副作用观察组（n=54）、模型组（n=18）、DXM疗效观察组（n=54）。根据DXM剂量不同将DXM副作用观察组和DXM疗效观察组分为1mg／kg、2mg／kg、3mg／kg三个亚组,每亚组18只,再根据观察时间的不同将每亚组分为观察14d、28d、56d三个小组,每小组6只。根据观察时间的不同将对照组和模型组分为观察14d、28d、56d三个小组,每小组6只。观察到期后,统计大鼠存活情况;大鼠左肺病理切片HE染色,光镜下观察肺部炎症和纤维化程度;对照组、模型组和DXM疗效观察组大鼠右肺测定羟脯氨酸（HYP）含量;大鼠肝、肾组织切片HE染色,光镜下观察其组织结构、炎症反应等变化。采用SPSS13．0软件,P〈0．05为差异有统计学意义。结果DXM副作用观察3mg／kg组的56d死亡率与相应对照组及DXM副作用观察1ms／kg组比较差异有统计学意义（P〈0．05）;DXM疗效观察3mg／kg组的56d死亡率与相应对照组、模型组、DXM疗效观察1mg／kg组比较差异有统计学意义（P〈0．05）。DXM在一定程度上能减轻博莱霉素致肺纤维化大鼠的肺泡炎和纤维化程度,但随其剂量的增加和用药时间的延长,其致肺部感染的机率也增加。绝大多数DXM疗效观察组HYP含量均较相应模型组为低,差异有统计学意义（P〈0．05）,三个剂量的DXM疗效观察组问差异无统计学意义（P〉0．05）。DXM副作用观察组和DXM疗效观察组大鼠肝组织普遍存在脂肪变性,而其肾组织可见肾小管内炎性细胞浸润。结论1mg／kg的DXM既能改善肺纤维化又未致严重感染和大鼠死亡率的增加,是治疗大鼠肺纤维化的有效安全剂量。     

博莱霉素致大鼠肺纤维化过程中肺泡巨噬细胞STAT1的活化和蛋白表达的研究

细胞因子的ＳＴＡＴ (ｓｉｇｎａｌｔｒａｎｓｄｕｃｅｒａｎｄａｃｔｉｖａｔｏｒｏｆｔｒａｎｓｃｒｉｐｔｉｏｎ)信号传导途径与疾病的发生、发展密切相关[1] ,但有关细胞因子的ＳＴＡＴ信号传导途径在肺间质病 (ＩＬＤ)发病机制中的作用 ,目前国内、外尚未见文献报道。我们以博莱霉素 (ＢＬＭ)致大鼠肺纤维化为模型 ,观察肺泡巨噬细胞(ＡＭ)内ＳＴＡＴ1活化和蛋白表达的动态变化 ,以探讨其在ＩＬＤ发病机制中的作用 ,为治疗ＩＬＤ探索新的途径。材料与方法　 1 肺纤维化动物模型的复制及分组、ＡＭ的分离与纯化、肺组织病理标本的制作参…     

低剂量博莱霉素致肺间质纤维化1例

1 病例资料 患者女,77岁,主诉干咳,进行性呼吸困难2个月于2005-03-24入解放军第202医院呼吸内科.患者于2005年1月无诱因出现阵发性干咳,偶有白痰,活动后呼吸困难,经抗感染对症治疗无好转,病情进行性加重,伴有胸痛,无咯血,无发热.既往有口腔乳头状瘤病史,2004年10月至2005年1月期间共应用博莱霉素80 mg治疗,口腔乳头状瘤消失.     

白三烯抑制剂对博莱霉素所致大鼠肺纤维化的干预作用

目的 观察白三烯抑制剂(LT-S)齐留通对博莱霉素(BLM)所致大鼠肺纤维化模型肺纤维化形成过程的影响.方法 54只SD雄性大鼠随机分为正常组(C组)、模型对照组(M组)和LT-S组(S组)3组,每组18只.S组于气管内滴注BLM(5 mg/kg)诱导肺纤维化,于造模当天开始每日给予齐留通100 mg/kg灌胃;M组以生理盐水代替齐留通灌胃;C组均用生理盐水代替BLM和齐留通.各组动物均于制模后的第7天、第14天和第28天分别随机处死6只动物,分取肺组织行病理切片苏木精-伊红染色和Masson染色观察肺泡炎和肺纤维化程度、碱水解法检测肺组织羟脯氨酸(Hyp)浓度、免疫组织化学技术检测肺组织α平滑肌肌动蛋白(α-SMA)和转化生长因子β1(TGF-β1)水平.结果 S组肺泡炎和肺纤维化程度及肺组织Hyp含量均显著低于M组,其TGF-β1和α-SMA在肺组织中的表达水平亦均显著低于M组.结论 LT-S可减轻BLM诱导的大鼠肺纤维化,并可能通过抑制TGF-β1蛋白表达而实现对成纤维原细胞增殖的抑制.     

趋化因子CXC受体3在博莱霉素诱导的肺纤维化中的作用

目的　采用趋化因子受体即CXCR3基因敲除小鼠 ,探讨CXCR3在博莱霉素诱导的肺损伤及纤维化中的作用。方法　采用基因打靶技术得到无CXCR3基因小鼠 6 2只 ,同时选择性别、年龄和体重配对的野生型小鼠 4 8只 ,随机分入不同的实验组及对照组。大鼠气管内注入博莱霉素0 0 2 5U。实验动物按要求处死后 ,取无血的肺组织切片 ,经 10 %甲醛固定后 ,用苏木精 伊红 (HE)和Massontrichrome染色 ,分别观察实验动物肺炎症和纤维化的程度 ;用浓盐酸消化肺组织提取羟脯氨酸并定量来表示肺胶原的含量 ;用磷酸盐缓冲液 (PBS)灌洗肺组织 ,酶联免疫吸附 (ELISA)法测定灌洗液中肿瘤坏死因子α(TNF α)、白细胞介素 5 (IL 5 )及转化生长因子 β(TGF β)的浓度 ;用流式细胞仪检测T细胞亚群。结果　气管内注入博莱霉素后 14d ,CXCR3基因敲除小鼠肺组织炎症程度及纤维化程度较野生型小鼠明显减轻。肺组织炎症程度评分和羟脯氨酸含量 (左肺 )在CXCR3基因敲除小鼠分别为 3 92± 0 37和 (6 7 0± 2 4 2 ) μg ,在野生型小鼠则分别为 5 33± 0 34和 (2 11 5± 2 4 2 )μg ,两组比较差异有统计学意义 (P分别 <0 0 5 ,<0 0 1) ;TGF β水平在CXCR3基因敲除小鼠为(2 2 11± 2 89) μg/L ,在野生型小鼠为 (5 388± 10 71) μg/L ,     

雷帕霉素对大鼠肺纤维化模型的干预作用及对转化生长因子表达的影响

目的研究雷帕霉素对大鼠肺纤维化模型的干预作用及可能的机制。方法150只SD大鼠采用随机数字表随机分成3组,每组50只：①雷帕霉素组。经气管内灌注博莱霉素诱导肺纤维化,随后每日用雷帕霉素口服溶液0．5mg／kg灌胃进行干预;②模型组,气管内灌注用博莱霉素,灌胃用生理盐水;③对照组,气管内灌注和灌胃均用生理盐水。各组动物均于气管内灌药后第3、7、14、28、56天分别处死10只。通过HE染色、Masson胶原染色、天狼猩红染色偏光法及测定肺组织羟脯氨酸浓度来观察肺泡炎和肺纤维化的程度。用逆转录-聚合酶链反应检测肺组织转化生长因子β1（TGF-β1）的mRNA表达。用免疫组化法检测大鼠肺组织TGF-β1蛋白的表达。结果模型组的肺组织羟脯氨酸含量和肺泡炎程度在各时间点均高于对照组,模型组的肺纤维化程度在第14、28和56天高于对照组（P〈0．05）;雷帕霉素组肺组织羟脯氨酸含量在第14、28和56天低于模型组,雷帕霉素组在第14和28天肺泡炎的程度低于模型组,雷帕霉素组在第28和56天肺纤维化程度低于模型组（P〈0．05）;模型组TGF-β1的mRNA表达在第3、7、14和28天高于对照组,雷帕霉素组TGF-β1的mRNA表达在第7和14天低于模型组（P〈0．05）。结论雷帕霉素能减轻博莱霉素诱导的大鼠肺纤维化,这种作用有可能部分通过抑制TGF-β1的表达而实现。     

前炎症性因子在博莱霉素所致肺纤维化中的中心作用

肺纤维化形成之前的炎症反应是致病的关键阶段,气道内博莱霉素激发啮齿动物的肺炎症反应是特发性肺纤维化(IPF)的代表性模型。阐明病变出现的不同细胞类型及可溶性调节因子之间的关系,使我们对肺纤维化的形成过程及其机制有更进一步地了解,可为今后IPF的防治开辟广阔前景。     

锌原卟啉对博莱霉素致大鼠肺纤维化模型的影响

目的观察血红素加氧酶-1（HO-1）抑制剂锌原卟啉（Znpp）对博莱霉素（BLM）致大鼠肺纤维化模型病理和病理生理改变的影响，探讨Znpp在BLM诱导肺纤维化发病中的作用。方法健康sD大鼠60只随机分三组：生理盐水（Ns）组、BLM组、Znpp组。气管内注入BLM制作肺纤维化模型。分别在第7天、第14天、第21天和第28天，每组处死5只大鼠，取肺组织HE染色，观察其病理改变；检测支气管肺泡灌洗液（BALF）中细胞计数及中性粒细胞百分比、转化生长因子-β（TGF—β）和总胆红素含量；检测肺组织中还原型谷胱甘肽（GSH）和羟脯氨酸（HYP）含量。结果病理显示BLM组和Znpp组肺组织在早期炎症阶段两者之间炎症程度无明显差异，但后期肺纤维化阶段时，BLM组纤维化程度显著高于Znpp组。用Znpp干预后没有抑制炎症细胞浸润肺组织，但有效抑制了TGF—β、总胆红素和HYP水平，减少了GSH耗竭。结论应用Znpp可以显著减轻BLM致大鼠肺纤维化，但其作用机制并不通过抑制早期炎症反应，而是通过其抗损伤、抗氧化、抗纤维化机制发挥治疗作用。     

The influence of dexamethasone on the proliferation and apoptosis of pulmonary inflammatory cells in bleomycin-induced pulmonary fibrosis in rats

OBJECTIVE: The aim of this study was to investigate the inhibitory effect of dexamethasone on the state of proliferation/apoptosis of the pulmonary inflammatory cells in a rat pulmonary fibrosis model induced by bleomycin. METHODOLOGY: Seventy-five pathogen-free Sprague-Dawley (SD) rats were randomly divided into three groups: control, bleomycin (BLM) and dexamethasone (DXM) groups with 25 rats in each group. Each group was then divided into five subgroups based on time of study (1-, 3-, 7-, 14- and 28-days). BAL fluid was obtained, the cells were counted and a differential was performed. A lower DNA content in apoptotic cells was detected and quantitated by flow cytometry. Haematoxylin and eosin staining was performed to observe the extent of alveolitis and fibrosis of lung tissue; the morphological changes in apoptotic cells were discerned by transmission electron-microscopy and a semi-quantitative assessment of apoptotic cells in lung tissue was performed using in situ TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick endlabelling). RESULTS: The total number of inflammatory cells and the percentage of neutrophils in BAL fluid in almost every subgroup of the DXM group were significantly lower than those in corresponding subgroups of the BLM group (P < 0.01). The percentages of apoptotic cells in BAL fluid in the 14-day and 28-day subgroups of the DXM group were higher than those in corresponding subgroups of the BLM group (P < 0.05). The peak of alveolitis in the DXM group shifted backward and the extent of fibrosis was less than that in the BLM group. The apoptosis index (AI) of inflammatory cells in each of the DXM subgroups was higher than that in corresponding BLM subgroups except for day 14. CONCLUSION: Dexamethasone can induce apoptosis of pulmonary inflammatory cells and reduce the extent of alveolitis and fibrosis in bleomycin-induced pulmonary fibrosis of rats.     

A novel single-chain-Fv antibody against connective tissue growth factor attenuates bleomycin-induced pulmonary fibrosis in mice

Background and objective: Connective tissue growth factor (CTGF) has been identified as playing critical roles in fibrosis and is a promising therapeutic target. In a previous study, we used a phage display library to develop a humanized single‐chain variable fragment antibody (scFv) against CTGF. In the present study, the protective effect of anti‐CTGF scFv against bleomycin (BL)‐induced pulmonary fibrosis was investigated in mice. Methods: The expression of α‐smooth muscle actin in human embryonic lung fibroblast (HELF) cells was analysed by western blotting. A mouse model of pulmonary fibrosis was established by tracheal injection of BL (5 mg/kg). Mice received anti‐CTGF scFv (4 mg/kg, three times a week) by i.v. injection. The effects of anti‐CTGF scFv were evaluated by leukocyte counts in BAL fluid, hydroxyproline measurements in lung tissue and pathological examination. Results: α‐Smooth muscle actin expression was decreased in HELF cells treated with anti‐CTGF scFv. Anti‐CTGF scFv significantly reduced the numbers of inflammatory leukocytes (total and differential count) in BAL fluid, as well as the hydroxyproline content of lung tissue. The severity of alveolitis and fibrosis in the mouse model was markedly attenuated by treatment with anti‐CTGF scFv. Conclusions: Anti‐CTGF scFv may potentially be developed as a useful inhibitor of pulmonary fibrosis.     

过氧化物酶体增殖物激活受体γ及其配体调节大鼠肺纤维化的作用机制

目的探讨过氧化物酶体增殖物激活受体γ（PPARγ）及其配体在博莱霉素诱导大鼠肺纤维化中的作用及参与机制。方法将24只雄性SD大鼠随机分为4组,即生理盐水对照组、罗格列酮对照组、博莱霉素组、罗格列酮干预组,经气管内注射博莱霉素建立肺纤维化模型。采用Masson染色观察肺组织形态学变化;碱水解法检测肺组织中羟脯氨酸含量;免疫组化及荧光定量RT-PCR检测PPARγ、MMP-9和TGF-β1的表达。结果气管内注入博莱霉素后,肺组织中羟脯氨酸含量、胶原沉积、MMP-9、TGF-β1及PPARγ表达较生理盐水对照组增加（P均〈0.05）;给予罗格列酮干预后,除PPARγ表达进一步增加,上述指标均下降（P均〈0.05）。相关性分析显示,博莱霉素组PPARγ蛋白水平与MMP-9和TGF-β1mRNA表达分别呈负相关（P均〈0.05）。结论 PPARγ参与了肺纤维化的发生;PPARγ及其配体罗格列酮可能通过抑制TGF-β1、MMP-9转录,从而减少胶原沉积,延缓博莱霉素诱导的肺纤维化进程。     

JAK/STAT1信号转导通路在博莱霉素致肺纤维化大鼠中的作用

目的 探讨蛋白酪氨酸激酶(JAK)信号传导子和转录活化子1(STAT1)信号转导通路在肺纤维化中的作用机制.方法 将30只Wistar大鼠随机分为博莱霉素(BLM)组和生理盐水(NS)组,分别于气管内灌注BLM及NS后第7、14、28天处死.右肺支气管肺泡灌洗,进行细胞分类、计数;左肺组织匀浆测定胶原含量;免疫组化法测定STAT1、血小板源性生长因子(PDGF)和纤溶酶原激活物抑制剂1(PAI-1)蛋白的表达.结果 BLM组肺组织胶原含量在7、14、28 d均明显高于NS组(P<0.01);BLM组肺组织STAT1、PDGF蛋白表达在第7天达高峰,之后下降,第28天时仍高于NS组(P<0.05),且与支气管肺泡灌洗液中的细胞总数呈正相关(r=0.880,P均<0.01);BLM组肺组织中PAI-1表达在第7天开始升高,第28天达高峰,且与肺组织中胶原含量呈正相关(r＝0.952,P<0.01).结论 JAK/STAT1信号转导通路可能通过调节STAT1、PDGF和PAI-1表达,参与肺纤维化的形成.     

Home versus hospital intravenous antibiotic therapy for acute pulmonary exacerbations in children with cystic fibrosis

To compare the effectiveness of home versus hospital intravenous (IV) antibiotic therapy for acute pulmonary exacerbations in children with cystic fibrosis (CF). A retrospective chart review was performed of 143 encounters for pulmonary exacerbations in 50 patients with CF. All encounters were categorized into two groups based on location of completion of antibiotic therapy: hospital group completed treatment in hospital (n = 64), home group completed treatment at home (n = 79). Percent change was calculated for forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1), forced expiratory flow rate between 25 percent and 75 percent of vital capacity (FEF(25-75%)), maximum forced expiratory flow (FEF(max)), oxygen saturation (O2 SAT), and weight. Means of percent change (PC) from the beginning to the end of IV antibiotic treatment in outcome variables were compared. Total duration of treatment was compared between the two groups. The two groups had no significant differences at baseline in all outcome variables. Treatment of exacerbations in both groups resulted in significant improvement of lung function, O2 SATS, and weight (P 相似文献   

The effect of melatonin on bleomycin-induced pulmonary fibrosis in rats

The present investigation was designed to determine the protective effects of melatonin against bleomycin (BLM)-induced oxidant lung toxicity. Wistar-albino rats were divided into four groups: saline (SA, 0.4 mL/animal), 1% ethanol-saline (ALC, 0.4 mL/animal), bleomycin sulphate (BLM, 10 mg/kg), or bleomycin sulphate + melatonin (BLM, 10 mg/kg + MLT, 10 mg/kg). All injections were given intraperitoneally (i.p.), twice weekly for a period of 3 wk (a total of seven injections for each group). Twenty-five days after BLM treatment, pulmonary fibrosis was assessed as hydroxyproline content in lung homogenates. Findings show that BLM-induced pulmonary injury resulted in increases in bronchoalveolar lavage fluid (BALF) biomarkers including total protein, lactate dehydrogenase (LDH), glutathione-peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT). Additionally, the levels of thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation (LPO), were also increased in BALF. Conversely, the level of glutathione (GSH) was reduced in BALF of BLM-treated rats. Melatonin provided protection against BLM-induced pulmonary fibrosis by suppressing oxidative stress. It abolished BLM-stimulated LPO and reversed the imbalance between oxidants and antioxidants in the BALFs. Results thus indicate that melatonin inhibits BLM-induced lung toxicity associated with oxidative damage.