复方鳖甲软肝片干预气道重塑作用机理的实验研究
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摘要
气道重塑即气道平滑肌的增生肥厚,细胞外基质的异常沉积,上皮下层纤维化等结构的改变,进而引起气道阻力增加,气道弹性降低,顺应性下降等,气道重构是COPD、哮喘主要病理特点之一。干预气道重塑就可以延缓气流受限的发展。实验中以气管内间隔14天、连续两次滴注内毒素的方法来建立气道纤维化模型,然后给予复方鳖甲软肝片干预,观察复方鳖甲软肝片干预气道重塑的疗效并从整体、细胞、分子水平阐明复方鳖甲软肝片干预气道重塑的机理。
方法:
1)健康SD大鼠共120只,分为正常组,假手术组,模型组,复方鳖甲软肝片高,中,低剂量组,醋酸泼尼松组,模型组动物为30只,其余每组15只,除假手术组、正常组外其余各组大鼠采用间隔14天,气管内连续两次滴注内毒素(1mg·Kg-1)的方法来建立动物模型,假手术组大鼠滴注等体积的生理盐水。造模后第28天开始给药。复方鳖甲软肝片高,中,低剂量组分别为1.4g/Kg.d,0.7g/Kg.d,0.35g/Kg.d,醋酸泼尼松组0.56 mg·kg-1·d-1,假手术组,模型组分别灌服等体积的生理盐水。治疗28天后取材,采用ELISA法检测各组动物血清和肺泡灌洗液中TNF-α、IL-8及IL-6含量;检测模型大鼠肺泡灌洗液中细胞总数及分类情况;采用生化分析方法检测肺组织匀浆中超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、丙二醛(MDA)和羟脯氨酸(HYP)含量;采用放免法检测各组大鼠血清中Ⅳ型胶原(Ⅳ-C)及层黏连蛋白(LN)和纤粘连蛋白(FN)的含量,同时取肺组织进行HE,Mallory染色并进行图象分析,分析胶原所占全肺面积比及各级细支气管周围上皮下胶原的面积;采用Western-blot法检测各组大鼠肺组织TGF-β1蛋白含量。
2)为进一步明确复方鳖甲软肝片干预气道重塑的机理,采用内毒素(1μg/ml)刺激的人支气管上皮细胞作为细胞模型,用不同剂量的复方鳖甲软肝片药物血清(1.4g/Kg.d,0.7g/Kg.d,0.35g/Kg.d)进行干预24小时,用RT-PCR的方法检测了支气管上皮细胞MMP-9mRNA、TIMP-1mRNA的表达;
3)采用SPSS10.0软件对相关实验数据进行统计学处理,求平均数,作单因素方差分析。
结果:
整体实验:
1.采用间隔14天,气管内连续两次滴注LPS的方法会引起大鼠血清、BALF中IL-8、TNFα含量的明显升高;而应用复方中药治疗后,可以显著降低肺泡灌洗液中IL-8、TNFα含量,也能降低血清中的IL-8、TNFα含量。
Airway remodeling is characterized by smooth muscle hyperplasia, mucus glands hypertrophy, subepithelial fibrosis, angiogenesis and change of extracellular matrix and associated with the long term decline in lung function, irreversible airflow obstruction, low airway elasticity and hyperresponsiveness. Airway remodeling is the main physiological change in Asthma and COPD. Preventing and treating airway remodeling can delay the development of the airflow obstruction. The rat model of airway fibrosis is established by intratrachea instilling LPS twice at 14 days interval, then is intervened by Fu-Fang-Bie-Jia-Ruan-Gan-Fang to observe the effect of herbal formula and elucidate its mechanism on airway remodeling intervention at cellular, subcellular and molecular levels. Methods
1. 120 male Sprague-Dawley rats were randomly divided into 7 groups (15 rats in each group, 30 rats in model group). Rats in the model control group, positive medicine group, and high, moderate and low Fu-Fang-Bie-Jia-Ruan-Gan-Pian groups were injected with 1mg.Kg~(-1) LPS two times at the interval of 14 days by trachea, and rats in sham-model control group with same volume normal saline. 28 day after the first injection, oral administration of drug daily until they were killed 1 day before. Fu-Fang-Bie-Jia-Ruan-Gan-Pian solution of different dosages (1.4g/Kg.d,0.7g/Kg.d,0.35g/Kg.d) was respectively given to rats in the high, moderate and low Fu-Fang-Bie-Jia-Ruan-Gan-Pian group by gavage, while equal volume of normal saline was given to those in the sham-model control group and model control group, and an equal volume of prednisone(0.56mg·kg-1·d-1) was saline was given to those in positive medicine control group.
After the 8w treatment, animals were sacrificed and the TNF-α,IL-8,IL-6 contents in serum and in BALF were analysed, as well as the SOD, GSH,MDA, HYP in lung tissue. The levels ofⅣ-collagen, laminin and fibronectin in serum were determined. The part lung samples were formalin-fixed, embedded in paraffin and stained with hematoxylin and eosin. Mallory stain were used for evaluate collagen. The other part samples were homogenated to analyse the protein of TGF-β1.
2. For the further elucidating the mechanism of airway remodeling intervened by Fu-Fang-Bie-Jia-Ruan-Gan-Pian, cell model of human bronchi epithelium stimulated by LPS were used as to analyse the MMP-9mRNA and TIMP-1mRNA expression intervened by Fu-Fang-Bie-Jia-Ruan-Gan-Fang drug serum.
方法:
1)健康SD大鼠共120只,分为正常组,假手术组,模型组,复方鳖甲软肝片高,中,低剂量组,醋酸泼尼松组,模型组动物为30只,其余每组15只,除假手术组、正常组外其余各组大鼠采用间隔14天,气管内连续两次滴注内毒素(1mg·Kg-1)的方法来建立动物模型,假手术组大鼠滴注等体积的生理盐水。造模后第28天开始给药。复方鳖甲软肝片高,中,低剂量组分别为1.4g/Kg.d,0.7g/Kg.d,0.35g/Kg.d,醋酸泼尼松组0.56 mg·kg-1·d-1,假手术组,模型组分别灌服等体积的生理盐水。治疗28天后取材,采用ELISA法检测各组动物血清和肺泡灌洗液中TNF-α、IL-8及IL-6含量;检测模型大鼠肺泡灌洗液中细胞总数及分类情况;采用生化分析方法检测肺组织匀浆中超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、丙二醛(MDA)和羟脯氨酸(HYP)含量;采用放免法检测各组大鼠血清中Ⅳ型胶原(Ⅳ-C)及层黏连蛋白(LN)和纤粘连蛋白(FN)的含量,同时取肺组织进行HE,Mallory染色并进行图象分析,分析胶原所占全肺面积比及各级细支气管周围上皮下胶原的面积;采用Western-blot法检测各组大鼠肺组织TGF-β1蛋白含量。
2)为进一步明确复方鳖甲软肝片干预气道重塑的机理,采用内毒素(1μg/ml)刺激的人支气管上皮细胞作为细胞模型,用不同剂量的复方鳖甲软肝片药物血清(1.4g/Kg.d,0.7g/Kg.d,0.35g/Kg.d)进行干预24小时,用RT-PCR的方法检测了支气管上皮细胞MMP-9mRNA、TIMP-1mRNA的表达;
3)采用SPSS10.0软件对相关实验数据进行统计学处理,求平均数,作单因素方差分析。
结果:
整体实验:
1.采用间隔14天,气管内连续两次滴注LPS的方法会引起大鼠血清、BALF中IL-8、TNFα含量的明显升高;而应用复方中药治疗后,可以显著降低肺泡灌洗液中IL-8、TNFα含量,也能降低血清中的IL-8、TNFα含量。
Airway remodeling is characterized by smooth muscle hyperplasia, mucus glands hypertrophy, subepithelial fibrosis, angiogenesis and change of extracellular matrix and associated with the long term decline in lung function, irreversible airflow obstruction, low airway elasticity and hyperresponsiveness. Airway remodeling is the main physiological change in Asthma and COPD. Preventing and treating airway remodeling can delay the development of the airflow obstruction. The rat model of airway fibrosis is established by intratrachea instilling LPS twice at 14 days interval, then is intervened by Fu-Fang-Bie-Jia-Ruan-Gan-Fang to observe the effect of herbal formula and elucidate its mechanism on airway remodeling intervention at cellular, subcellular and molecular levels. Methods
1. 120 male Sprague-Dawley rats were randomly divided into 7 groups (15 rats in each group, 30 rats in model group). Rats in the model control group, positive medicine group, and high, moderate and low Fu-Fang-Bie-Jia-Ruan-Gan-Pian groups were injected with 1mg.Kg~(-1) LPS two times at the interval of 14 days by trachea, and rats in sham-model control group with same volume normal saline. 28 day after the first injection, oral administration of drug daily until they were killed 1 day before. Fu-Fang-Bie-Jia-Ruan-Gan-Pian solution of different dosages (1.4g/Kg.d,0.7g/Kg.d,0.35g/Kg.d) was respectively given to rats in the high, moderate and low Fu-Fang-Bie-Jia-Ruan-Gan-Pian group by gavage, while equal volume of normal saline was given to those in the sham-model control group and model control group, and an equal volume of prednisone(0.56mg·kg-1·d-1) was saline was given to those in positive medicine control group.
After the 8w treatment, animals were sacrificed and the TNF-α,IL-8,IL-6 contents in serum and in BALF were analysed, as well as the SOD, GSH,MDA, HYP in lung tissue. The levels ofⅣ-collagen, laminin and fibronectin in serum were determined. The part lung samples were formalin-fixed, embedded in paraffin and stained with hematoxylin and eosin. Mallory stain were used for evaluate collagen. The other part samples were homogenated to analyse the protein of TGF-β1.
2. For the further elucidating the mechanism of airway remodeling intervened by Fu-Fang-Bie-Jia-Ruan-Gan-Pian, cell model of human bronchi epithelium stimulated by LPS were used as to analyse the MMP-9mRNA and TIMP-1mRNA expression intervened by Fu-Fang-Bie-Jia-Ruan-Gan-Fang drug serum.
引文
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