中药地龙对哮喘大鼠气道重建的影响
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摘要
目的：观察中药地龙对哮喘大鼠气道重建的形态结构的影响,探讨中药地龙对哮喘大鼠气道重建的作用机制。
方法：随机将80只230-330g雄性大鼠分成正常对照组,模型组,小剂量组,中剂量组,大剂量组,Dex组,中剂量+Dex组。建立一种能反应人类哮喘特征、具有气道重建病理改变的大鼠哮喘模型；观察各组大鼠肺泡灌洗液和下腔静脉血中的白细胞、嗜酸性粒细胞的数量；各组大鼠肺组织切片做HE染色,用图像分析系统测量气道内径与外径比值,气道平滑肌、基底膜厚度；免疫组化法检测各组大鼠肺组织TGF-β1、MMP9/TIMP-1蛋白表达；ELISA方法检测各组大鼠气道平滑肌匀浆uPA, PAI-1的表达。RT-PCR技术检测各组大鼠气道平滑肌匀浆c-Myc的表达；原位杂交技术检测各组大鼠肺组织c-Myc的表达。
结果：1.中药地龙可降低哮喘大鼠下腔静脉血及肺泡灌洗液中嗜酸性粒细胞的数量；2.中药地龙可抑制气道壁的增厚,可抑制平滑肌和基底膜的增厚,此抑制作用呈剂量依赖性；3.中药地龙可抑制哮喘大鼠气道壁TGF-p,的表达,MMP-9,TIMP-1的表达；4.中药地龙可抑制uPA, PAI-1的表达；5.中药地龙可减少气道c-Myc的表达。6.气道基底膜的增厚与血液中嗜酸性粒细胞的数量、气道TGF-p,及MMP-9免疫组化法检测阳性面积比、气道平滑肌匀浆uPA浓度之间呈正相关,与气道c-Myc原位杂交法检测灰度值呈负相关,说明TGF-β1、MMP-9、uPA、c-Myc在哮喘气道重建中发挥重要作用。
结论：在哮喘大鼠气道重建形成早期应用中药地龙,可明显预防或延缓气道重建的发生；联合应用地塞米松对哮喘大鼠气道重建的预防及治疗作用较单独应用地塞米松效果更为显著。
Objective To study the effect and possible mechanism of Traditional Chinese drug Dilong and/or Dexamethasone on airway remodeling in experimental rat model of asthma.
Methods 80 male SD rats(230-330g) were randomly divided into seven groups: normal control group, asthmatic group, low-dosage Dilong group, middle-dosage Dilong group, high-dosage Dilong group, dexamethasone (Dex) group, middle-dosage Dilong and dexamethasone (Dex) group. The chronic asthma model was established that was able to reflect human asthma characteristics and pathological changes of airway remodeling. The numbers of leukocytes and eosinophils in the bronchoalveolar lavage(BALF) fluid and inferior vena cava blood were counted. Lung tissues were sliced and stained with HE. The following morphometric parameters were measured:thickness of airway wall basement membrane, thickness of airway smooth muscle, the ratio of inner diameter/outer diameter of airway wall. The expressing levels of TGF-β1、MMP9/TIMP-1 were evaluated by immunoreactivity. The expressing levels of uPA, PAI-1 in airway smooth muscle homogenates were evaluated by ELISA. The expressing level of c-myc in airway smooth muscle homogenates was evaluated by RT-PCR. The expressing level of c-myc in lung tissues was evaluated by in situ hybridization.
Results 1. Dilong could decrease the number of eosinophils in the inferior vena cava blood and the bronchoalveolar lavage(BALF) fluid.2. Dilong could inhibit the thickening of airway wall, as well as airway wall basement membrane and airway smooth muscle. Combined dexamethasone could reinforce Dilong's effects.3. Dilong could decrease the expressing levels of TGF-β1、MMP9/TIMP-1.4. Dilong could decrease the expressing levels of uPA, PAI-1.5. Dilong could decrease the expressing level of c-myc. 6. There is a positive correlation between the cellularity of eosinophils, the thickness of airway wall basement membrane, thickness of airway smooth muscle and TGF-β1, uPA, c-myc.
Conclusion Dilong could inhibit and partly reverse the airway remodeling at an early stage. Dilong combined with dexamethasone could reinforce the effects.
方法：随机将80只230-330g雄性大鼠分成正常对照组,模型组,小剂量组,中剂量组,大剂量组,Dex组,中剂量+Dex组。建立一种能反应人类哮喘特征、具有气道重建病理改变的大鼠哮喘模型；观察各组大鼠肺泡灌洗液和下腔静脉血中的白细胞、嗜酸性粒细胞的数量；各组大鼠肺组织切片做HE染色,用图像分析系统测量气道内径与外径比值,气道平滑肌、基底膜厚度；免疫组化法检测各组大鼠肺组织TGF-β1、MMP9/TIMP-1蛋白表达；ELISA方法检测各组大鼠气道平滑肌匀浆uPA, PAI-1的表达。RT-PCR技术检测各组大鼠气道平滑肌匀浆c-Myc的表达；原位杂交技术检测各组大鼠肺组织c-Myc的表达。
结果：1.中药地龙可降低哮喘大鼠下腔静脉血及肺泡灌洗液中嗜酸性粒细胞的数量；2.中药地龙可抑制气道壁的增厚,可抑制平滑肌和基底膜的增厚,此抑制作用呈剂量依赖性；3.中药地龙可抑制哮喘大鼠气道壁TGF-p,的表达,MMP-9,TIMP-1的表达；4.中药地龙可抑制uPA, PAI-1的表达；5.中药地龙可减少气道c-Myc的表达。6.气道基底膜的增厚与血液中嗜酸性粒细胞的数量、气道TGF-p,及MMP-9免疫组化法检测阳性面积比、气道平滑肌匀浆uPA浓度之间呈正相关,与气道c-Myc原位杂交法检测灰度值呈负相关,说明TGF-β1、MMP-9、uPA、c-Myc在哮喘气道重建中发挥重要作用。
结论：在哮喘大鼠气道重建形成早期应用中药地龙,可明显预防或延缓气道重建的发生；联合应用地塞米松对哮喘大鼠气道重建的预防及治疗作用较单独应用地塞米松效果更为显著。
Objective To study the effect and possible mechanism of Traditional Chinese drug Dilong and/or Dexamethasone on airway remodeling in experimental rat model of asthma.
Methods 80 male SD rats(230-330g) were randomly divided into seven groups: normal control group, asthmatic group, low-dosage Dilong group, middle-dosage Dilong group, high-dosage Dilong group, dexamethasone (Dex) group, middle-dosage Dilong and dexamethasone (Dex) group. The chronic asthma model was established that was able to reflect human asthma characteristics and pathological changes of airway remodeling. The numbers of leukocytes and eosinophils in the bronchoalveolar lavage(BALF) fluid and inferior vena cava blood were counted. Lung tissues were sliced and stained with HE. The following morphometric parameters were measured:thickness of airway wall basement membrane, thickness of airway smooth muscle, the ratio of inner diameter/outer diameter of airway wall. The expressing levels of TGF-β1、MMP9/TIMP-1 were evaluated by immunoreactivity. The expressing levels of uPA, PAI-1 in airway smooth muscle homogenates were evaluated by ELISA. The expressing level of c-myc in airway smooth muscle homogenates was evaluated by RT-PCR. The expressing level of c-myc in lung tissues was evaluated by in situ hybridization.
Results 1. Dilong could decrease the number of eosinophils in the inferior vena cava blood and the bronchoalveolar lavage(BALF) fluid.2. Dilong could inhibit the thickening of airway wall, as well as airway wall basement membrane and airway smooth muscle. Combined dexamethasone could reinforce Dilong's effects.3. Dilong could decrease the expressing levels of TGF-β1、MMP9/TIMP-1.4. Dilong could decrease the expressing levels of uPA, PAI-1.5. Dilong could decrease the expressing level of c-myc. 6. There is a positive correlation between the cellularity of eosinophils, the thickness of airway wall basement membrane, thickness of airway smooth muscle and TGF-β1, uPA, c-myc.
Conclusion Dilong could inhibit and partly reverse the airway remodeling at an early stage. Dilong combined with dexamethasone could reinforce the effects.
引文
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