Somatostatin analogs for idiopathic pulmonary fibrosis therapy

Background: Idiopathic pulmonary fibrosis (IPF) is a potentially lethal disease characterized by diffuse multifocal fibrosis. SOM230 (also known as pasireotide), a somatostatin analog, is a potential antifibrotic therapy in early evaluative phase. Objective: Evaluation of data on the role of somatostatin receptors in pulmonary fibrosis and of in vivo and in vitro SOM230 antifibrotic activities. Methods/results: This study assessed somatostatin receptor expression in human normal and IPF lungs, and in animal lungs with bleomycin-induced fibrosis, as well as the effects of SOM230. The overall overexpression of somatostatin receptor subtype 2 and the anti-inflammatory/antifibrotic activities of SOM230 were demonstrated. Conclusion: These results are promising for further preclinical and clinical testing of SOM230 as an antifibrotic therapy.     

Effect of chlorpromazine on proline absorption across rat jejunum

The effect of chlorpromazine on proline absorption across jejunum in anaesthetized rats was investigated. Intravenous infusion of chlorpromazine reduced significantly (P less than 0.01) proline absorption across the jejunum. Intraluminal perfusion of chlorpromazine into the jejunal segment reversed net absorption of proline to net secretion. Net water absorption was increased significantly (P less than 0.01) when chlorpromazine was infused intravenously or perfused intraluminally. Unidirectional influx of proline across the mucosal surface was significantly inhibited (P less than 0.01) after preincubation with 1 mM chlorpromazine.     

参芎葡萄糖在治疗肺纤维化中的作用

目的:研究中药参芎葡萄糖在大鼠肺纤维化治疗中的作用.方法:①实验分组:先将健康Wistar大鼠60只随机分两组,对照组20只、模型组40只,若模型成功将模型组再分为模型组(单纯肺纤维化组)、参芎葡萄糖治疗肺纤维化组(简称参芎组),地塞米松治疗肺纤维化组(简称地塞组).②模型制备:采用气管内注射博来霉素(BLM-A5)建...     

Effects and mechanisms of pirfenidone,prednisone and acetylcysteine on pulmonary fibrosis in rat idiopathic pulmonary fibrosis models

Context: Previous studies have reported that caveolin-1 (Cav-1) is associated with lung fibrosis. However, the role of Cav-1 expression in pirfenidone-treated idiopathic pulmonary fibrosis (IPF) is unknown.

Objective: This study investigated Cav-1 expression in pirfenidone-treated IPF, and compared the effects of pirfenidone with acetylcysteine and prednisone on IPF.

Materials and methods: Rat IPF model was established by endotracheal injection of 5?mg/kg bleomycin A5 into the specific pathogen-free Wistar male rats. Pirfenidone (P, 100?mg/kg once daily), prednisone (H, 5?mg/kg once daily) and acetylcysteine (N, 4?mg/kg 3 times per day) were used to treat the rat model by intragastric administration for 45 consecutive days, respectively. The normal rats without IPF were used as the controls. After 15, 30 and 45 days of drug treatment, lung histopathology was assessed. The expression of Cav-1 was determined using real-time quantitative PCR and Western blot; the expression of tumour necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor (PDGF) was determined by enzyme-linked immunosorbent assay.

Results: After 15, 30 and 45 days of drug treatment, comparison of the three drug-treated groups with the model group showed significantly lower (p?p?p?r?=??0.506, p?r?=?-0.676, p?r?=??0.590, p?r?=??0.530, p?r?=??0.553, p?Discussion and conclusion: Pirfenidone, prednisone and acetylcysteine can inhibit airsacculitis and pulmonary fibrosis in rat IPF models, which may be related with enhanced caveolin-1, reduced TNF-α, TGF-β1, PDGF.     

卡托普利对博来霉素诱导大鼠肺纤维化的影响

目的探讨博来霉素（bleomycin）中毒肺BLM纤维化机制及卡托普利对BLM中毒肺纤维化的干预作用。方法 60只SD大鼠随机分为3组：正常对照（control）组、单纯BLM染毒（BLM）组和BLM染毒卡托普利（captopril,CPT）治疗（BLM＋CPT）组。14 d后处死各组动物,记录肺系数;病理组织学检查。结果 BLM染毒后大鼠肺系数增大,肺泡炎、肺纤维化程度积分明显增高。CPT均明显减轻了大鼠肺损伤、肺纤维化程度。结论 CPT对BLM中毒大鼠肺损伤、肺纤维化程度有一定改善作用,可能与其抑制血管紧张素Ⅱ有关。     

白藜芦醇对博莱霉素诱导的小鼠肺纤维化的作用

目的:探讨白藜芦醇(Res)对博莱霉素(BLM)致肺纤维化(PF)的治疗作用.方法:复制小鼠博莱霉素致PF模型,采用光镜观察组织学改变.测定肺组织羟脯氨酸(HyP)、超氧化物歧化酶(SOD)、丙二醛(MDA)以反映肺细胞损伤及PF的程度.结果:Res能显著降低实验性PF小鼠肺组织中Hyp、MDA的含量,显著提高小鼠肺组织的SOD活力.病理组织学检查亦表明,Rea能明显改善肺泡炎症程度和PF程度.结论:Res对实验性小鼠PF具有一定的治疗作用.     

大鼠肺纤维化发生发展过程中肺组织环核苷酸的变化及其作用研究

目的 观察纤维化肺组织环核苷酸(cAMP和cGMP)的动态变化,研究环核苷酸的信号作用机制.方法 48只SD大鼠分为对照组、模型组和干预组.模型组和干预组经气管内注入BLM(Smg/kg,0.2～0.3m1)诱导形成肺纤维化,干预组每日经胃管灌注卡托普利(CPT)60mg/kg·d.各组动物于3、7、14、21d各处死4只,观察肺组织病理改变,并同位素放免检测肺组织环核苷酸水平.结果 干预组肺泡炎和肺纤维化程度均轻于模型组;模型组和干预组肺组织cAMP表达呈进行性下降趋势,cGMP表达则正好相反;干预组环核苷酸表达改变小于模型组.结论 纤维化肺组织的cAMP表达降低,cGMP表达升高;肺组织环核苷酸的表达与纤维化的严重程度有关;肺纤维化有效干预提高肺组织cAMP表达,抑制cGMP表达.     

Effect of Rho-ROCK signaling pathway on pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung scarring, reduced median survival, poor prognosis and limited therapeutic options, leading to great need for new pharmacologic therapies. In recent years, researchers have found that Rho-ROCK signaling pathway may be a new drug target in the prevention of IPF. This article reviewed the role of Rho-ROCK pathway in pulmonary fibrosis and the application of ROCK inhibitors in experimental models of IPF. Multiple lines of evidence therefore indicated that ROCK inhibition has great potential to be a powerful therapeutic tool in the prevention and treatment of IPF in clinic.     

Effect of proline administration on rat behavior in aversive and nonaversive tasks

Sustained levels of proline comparable to those of human type II hyperprolinemia were achieved in blood and brain of rats subcutaneous proline administration twice a day from the 6th till the 28th day of life. Control rats were treated with saline in the same volumes. Behavioral studies using aversive and nonaversive tasks were performed one week or one month after treatment. Proline treatment did not affect rats' performance in the inhibitory avoidance task, but reduced significantly habituation in the open field. Our results seem to indicate that early postnatal administration of proline to rats affects habituation to a novel environment. If this happens to be so the present tendency to consider hyperprolinemia as a benign condition should be revised.     

蛋白酶激活受体-1在肺纤维化大鼠肺组织中的表达

目的探讨在博莱霉素所致大鼠肺纤维化模型肺组织中蛋白酶激活受体-1的表达。方法将体重180-250g的SD清洁级雄性大鼠48只,按完全随机方法分为对照组及博莱霉素(BLM)组,BLM组大鼠气管内注入0.9-1.25ml博莱霉素A5(BLMA5,5mg/kg),对照组在同样条件下向气管内注入等量的生理盐水。两组动物于气管灌注后第7、14、28、40d分别随机处死6只。组化方法检测肺组织PAR-1的表达;Masson染色检测肺组织纤维化,按Ashcroft评分法,评估肺纤维化的严重程度,结果(1)对照组无明显胶原沉积,BLM组随着时间的延长,可见明显胶原沉积,BLM组/对照组两组在第7、14、28、40d肺间质纤维化Ashcroft评分分别为24±3.72/3±0.63、46.4±4.09/4±0.63、69.3±3.78/3±1.41、64.5±5.96/3±1.67,两组有显著性差异(P﹤0.05)。(2)BLM组/对照组两组在第7、14、28、40d平均每高倍镜视野肺组织PAR-1阳性细胞数分别为:9.93±1.47/2.5±1.52、16.67±2.16/1.83±1.17、17.67±2.16/2.17±0.75、16.0±2.28/2.17±1.17。BLM组各时间点肺组织PAR-1阳性细胞数较正常对照组增多,两组具有显著统计学差异(P﹤0.05)。(3)肺间质纤维化程度与PAR-1阳性细胞数呈正相关(r=0.76)。结论博莱霉素所致大鼠肺纤维化模型肺组织中蛋白酶激活受体-1的表达增强;蛋白酶激活受体-1的表达可能在博来霉素所致肺纤维化中其重要作用。     

硫化氢在大鼠肺纤维化中的表达

目的：研究内源性硫化氢（H2S）在大鼠肺纤维化中的表达。方法：①实验分组：将健康Wistar大鼠30只随机分为对照组、模型组（肺纤维化组）。②模型制备：采用气管内注射博来霉素（BLM—A5）建立肺纤维化模型。③评价：通过对大鼠肺组织形态学,病理学观察,评价模型成功与否。④观察指标：于试验的第7、14、28天时每组分别处死5只大鼠。采用去蛋白分析方法测量血浆中H2S含量．取肺组织行HE染色和Mallory三色染色。结果：①模型组大鼠血浆中H2S含量第7天时较对照组降低50％．第14天时降低32％．第28天时降低21％（P〈0．01）。②造模后首先出现肺泡炎。随着时间的延长,炎性反应逐渐减轻,肺纤维化程度逐渐加重。结论：①经过观察．采用气管内注射博来霉素（BLM—A5）的方法成功的制备了大鼠肺纤维化模型。②正常大鼠体内存在一定量的硫化氢。③硫化氢参与了大鼠肺纤维化发展的病理生理过程。     

罗格列酮对大鼠肺纤维化细胞模型干预治疗的疗效观察

目的采用转化生长因子（TGF-β1）诱导大鼠肺成纤维细胞,给予罗格列酮干预,明确其对大鼠肺纤维化的影响。方法以组织贴块法培养肺成纤维细胞,分为0.4%血清对照组（空白对照组）、TGF-β1模型组（模型组）、TGF-β1＋不同浓度罗格列酮干预组（干预组）,分别检测大鼠肺纤维化细胞代谢活性及Ⅰ、Ⅲ型胶原合成情况。结果不同浓度罗格列酮干预组OD值与模型组比较都有所下降（P〈0.05）,其中罗格列酮浓度在10μmol/L时OD值与模型组比较下降最为明显,不同罗格列酮浓度组间OD值差异无显著性（P〉0.05）。10μmol/L罗格列酮干预组与模型组相比较,Ⅰ型、Ⅲ型胶原表达下降,差异具有显著性（P〈0.05）。结论罗格列酮可以抑制TGF-β1诱导的大鼠肺成纤维细胞增殖和Ⅰ型、Ⅲ型胶原的合成。     

Analgesic activity of dermorphin and its proline analogs

Dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2; DM) and its analogs obtained via stereochemical transformation of L-Pro6 to D-Pro6 peptide in DM ([Dpro6]DM) and via dehydration of L-Pro6 peptide ([dHPro6]DM) were characterized with respect to the analgesic activity in rats tested under conditions corresponding to various levels of pain sensitivity organization. The drugs were introduced by intraperitoneal injections in various doses (0.1, 1.0, and 10 mg/kg). In the case of acetic-acid induced convulsions (writhing), DM and [Dpro6]DM produced analgesic action in the minimum dose, while the analogous effect of [dHPro6]DM was observed only in greater doses. In the tail-clamp (Haffner) test, DM and [Dpro6]DM also inhibited nociception while the latter compound was ineffective. In the grid-shock test, [Dpro6]DM showed a higher activity than [dHPro6]DM, whereas DM did not produce analgesic action. Thus, all the studied peptides exhibit pronounced analgesic activity, and the replacement of L-Pro6 in DM by its stereomer D-Pro is more effective than the substitution of dHPro6.     

银杏叶制剂对肺间质纤维化的治疗作用探讨

<正> 肺间质纤维化目前发病机制尚未完全明了,近年该病发生有增多趋势,临床疗效差,患者往往因呼吸衰竭而死亡。因此,对肺间质疾病的发病机制和治疗的研究日益受到重视,希望探索出治疗肺纤维化的新的途径。银杏叶制剂就是其中之一。1 肺间质纤维化的发病机制目前,肺间质纤维化发病机制尚未完全明了,肺间质纤维化发病过程可概括为肺泡炎和肺纤维化两个阶段。肺实质损伤发生可能与遗传因素、病毒感染、免疫功能异常等因素有关。致肺纤维化的损伤因素首先引起肺泡上皮细胞和毛细血管内皮细胞损     

苦参碱对实验大鼠肝纤维化的影响

目的 :研究苦参碱对实验大鼠肝纤维化的防治作用 ,并探讨其可能的机制。方法 :应用四氯化碳诱导大鼠实验性肝纤维化 ,以苦参碱防治。观察3,6 ,12wk时溶剂对照组、四氯化碳组、苦参碱组血清丙氨酸转氨酶 (ALT)、透明质酸 (HA)、肝组织羟脯氨酸 (HyP)含量以及肝脏病理变化。结果 :苦参碱能显著减轻实验大鼠肝细胞变性、坏死及纤维组织的形成 ,同时能降低不同实验阶段血清ALT(P <0 .0 1) ,HA(P <0 .0 1)以及肝组织中HyP含量 (P <0 .0 5)。结论 :苦参碱有保护肝细胞 ,减轻肝细胞坏死 ,防治四氯化碳诱发的肝纤维化的作用。     

芒果三芪肺纤方对博莱霉素致小鼠肺纤维化作用研究

目的 观察芒果三芪肺纤方对博莱霉素诱导小鼠肺纤维化的改善作用。方法 昆明小鼠随机分为对照组,模型组,地塞米松（阳性药,1 mg/kg）组,芒果三芪肺纤方高、中、低剂量（以生药计5.00、3.30、1.65 g/kg）组,通过鼻腔1次性滴入6 mg/kg盐酸博莱霉素制备小鼠肺纤维化模型,对照组滴入等体积的生理盐水。于造模后第14天开始ig给药,每天给药1次,连续给药14 d后处死小鼠,试剂盒法测定肺组织匀浆中的羟脯氨酸（HYP）、丙二醛（MDA）、白介素-1β（IL-1β）水平和超氧化物岐化酶（SOD）活力;HE染色观察肺组织病理切片,Masson染色观察胶原纤维的分布情况。结果 与模型组比较,芒果三芪肺纤方高、中、低剂量组小鼠HYP和IL-1β水平均显著降低（P<0.01）,SOD活力显著提高（P<0.05、0.01）,高和中剂量组小鼠MDA水平显著降低（P<0.05、0.01）;HE和Masson染色显示,芒果三芪肺纤方组肺泡炎损伤和肺纤维化病变程度明显减轻（P<0.01）,高剂量组效果最好。结论 芒果三芪肺纤方通过提高SOD活力、降低MDA水平,发挥抗自由基损伤作用;降低HYP的水平,减少纤维蛋白的形成;降低IL-1β水平,发挥抗炎作用;显著减轻肺泡炎症损伤、抑制肺纤维化病变程度,对博莱霉素诱导的小鼠肺纤维化具有很好的改善作用。     

Evaluation of potential anti-fibrotic effect of oleuropein on bleomycin-induced pulmonary fibrosis in rat

Abstract

The etiology of idiopathic pulmonary fibrosis (IPF) is not well known, however it is a final response of frequent injuries to endothelial and epithelial cells that cause influx of the inflammatory cells. Bleomycin (BLM), a chemotherapeutic agent that causes lung fibrosis in human patients has been applied extensively in rodent models to inducing IPF. Moreover, oxidative stress and production of reactive oxygen species (ROS) have been involved in the pathogenesis. We aimed to investigate the effect of main olive antioxidant and anti-inflammatory polyphenol constituent, oleuropein (OLE), on BLM-induced fibrosis model. Female Wistar rats were divided into six groups (n?=?8). In this study, whereas negative group only received vehicle and treatment groups received OLE (20, 40, and 80?mg kg^?1) orally. Also, positive control group received intratracheally (IT), single dose BLM (7.5?U kg^?1), prednisolone (10?mg/kg) as standard cure a week before and 3 weeks after IT-BLM. At 21th day of experiment, IL-13, TNF, TGF-β, and PDGF in the bronchoalveolar fluid (BALF), lung content hydroxyproline (HP), and malondialdehyde (MDA) were quantified. Histopathological changes in lungs were investigated too. IL-13, TNF, TGF-β₁, PDGF in BALF, lung HP (collagen index), and MDA content in BLM-injected group was significantly higher than the control group (p?<?.05). In contrast, rats treated with OLE showed obviously lesser contents. Also, the histopathological observation confirms these findings. The results indicate that treatment by OLE may inhibit production of anti-inflammatory cytokines and ROS, and thus could be a useful medicine for managing fingagin disorders.