肺表面活性物质对慢阻肺鼠模型基质金属蛋白酶及抑制剂影响的研究
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摘要
目的肺表面活性物质(Pulmonary suffactant，PS)在生理情况下具有降低肺泡表面张力、抗水肿、稳定小气道、抗氧化和蛋白酶所致肺损伤、调节局部免疫和炎症反应等作用，PS合成分泌障碍参与气道阻塞发病过程，通过补充外源性PS或研制可能刺激内源性PS合成分泌的药物，可能会开辟治疗COPD的新途径。本文主要研究外源性PS对被动吸烟致慢性阻塞性肺病大鼠模型的肺功能、基质金属蛋白酶9(MMP-9)及金属基质蛋白酶组织抑制剂(TIMP-1)等的影响，探讨其对慢性阻塞性肺病(COPD)的治疗作用，为其在COPD临床治疗中的广泛应用提供理论依据。
方法30只健康雄性Wistar大鼠随机分为三个实验组：健康对照组(n=10)、COPD模型组(n=10)和PS干预组(n=10)。健康对照组：正常喂养，不做任何干预；COPD模型组：采用香烟熏吸加气道内注入脂多糖法建立大鼠COPD模型，并于实验第2、3、5、6周行假手术做为对照；PS干预组建立模型方法同COPD模型组，但于实验第2、3、5、6周给予气管内注入外源性PS。6周后，检测各组动物的肺功能、动脉血气；光镜观察肺组织病理学改变并应用显微—微机图像分析系统进行形态学定量检测；应用免疫组化方法检测基质金属蛋白酶9及金属基质蛋白酶组织抑制剂(TIMP-1)的阳性表达。
结果该法建立被动吸烟致肺损伤大鼠模型的肺组织病理学改变基本符合人类COPD组织病理学改变特点。大鼠肺功能检测结果：COPD模型组呼气阻力(Re)、FEV_(0.3)、FEV_(0.3)／FVC与健康对照组比较有显著性差异(P＜0.01)；与PS干预组比较有显著性差异(P＜0.01)；PS干预组与健康对照组比较，FEV_(0.3)／FVC差别有统计学意义(P＜0.05)，Re及FVE_(0.3)比较无显著性差异(P＞0.05)。动脉血气结果：COPD模型组PaO_2、PaCO_2与健康对照组比较有显著性差异(P＜0.01)；与PS干预组比较有显著性差异(P＜0.05)；PS干预组与健康对照组比较，PaO_2、PaCO_2差别有统计学意义(P＜0.05)。肺组织病理学改变：COPD模型组肺平均内衬间隔(MLI)、平均肺泡数(MAN)、肺泡气腔与肺总面积比(PAA)％]与健康对照组比较有显著性差异(P＜0.01)；与PS干预组比较有显著性差异(P＜0.01)；健康对照组MLI、PAA与PS干预组比较有显著性差异(P＜0.01)。COPD模型组MMP-9、TIMP-1表达增强，二者相对阳性面积及MMP-9／TIMP1与健康对照组比较有显著性差异(P＜0.01)，与PS干预组比较有显著性差异(P＜0.01)，PS干预组MMP-9、TIMP-1表达与健康对照组比较仍增强有显著性差异(P＜0.01)，但MMP-9／TIMP1与健康对照组比较无显著性差异
结论被动吸烟及气管内注入脂多糖可引起肺部损伤，导致肺功能下降，血气指标发生改变，肺组织发生损伤，MMP-9，TIMP-1表达增强，MMP-9／TIMP-1比例失衡。应用外源性PS进行干预可对COPD大鼠的气道炎症有明显的抑制作用，减轻肺组织的损伤，MMP-9表达减少，MMP-9／TIMP-1比例趋于平衡，并改善肺功能，对COPD的发生起到预防保护作用，延缓病情发展。
【OBJECTIVE】To investigate the expression of matrix metalloproteinases-9(MMP-9)and his tissue inhibitor (TIMP-1) in the lung of smoke-induced chronic obstructivepulmonary disease(COPD) in rats and the therapeutic effect of pulmonary surfactant.
【METHODS】COPD animal model was established by smoke inhalations andintratracheal instillations of lipopolysaccharide in Wistar rats. Thirty Wistar ratswere randomly divided into 3 groups as follows: normal group(N), controlgroup(C),and treatment group(T).The last two groups received smoke inhalationsdaily for 6 weeks and received intratracheal instillations of lipopolysaccharide twice,one of which received exogenous pulmonary surfactant treatment(100mg/Kg BW) inthe 2nd,3rd,5th,6th week(4 times) by intratracheal instillation before exposure tocigarette smoking. Lung function test、blood gas analysis、light microscopyobservations were performed in each group. Pulmonary mean linear intercept (MLI),mean alveolar numbers (MAN), and pulmonary alveolar area (PAA) was measured byimage analysis. The expression of MMP-9 and TIMP-1 were observed byimmunohistochemistry.
【RESULTS】Smoking for 6 weeks and instillations of lipopolysaccharide twiceresulted in chronic bronchitis and emphysema(Fig 2,5). MLI and PAA increased andMAN decreased in the two experimental groups compared with in the normal group(P＜0.01)(table 1).FEV_(0.3) and FEV_(0.3)/FVC decreased and Re increased in the twoexperiment groups compared with in the normal group (P＜0.01)(table 2).PaO_2decreased and PaCO_2 increased in the two experimental groups compared with in thenormal group(table 3). Administration of exogenous pulmonary surfactant for 4times resulted in statistically significant inhibition of pulmonary injury (Fig 3, 6).MLI and PAA decreased and MAN increased in T compared with in C(P＜0.01).Thelung function was improved in T compared with in C(P＜0.01): FEV_(0.3) andFEV_(0.3)/FVC increased and Re decreased in T, also the PaO_2 increased and PaCO_2decreased. The expresstion of MMP-9 increased significantly (P＜0.01) and the ratioMMP-9/TIMP-1 was unbalance in model group (Fig8、11) with N(Fig7、10).Administration of exogenous pulmonary surfactant for 4 times resulted in statisticallysignificant inhibition of pulmonary injury. The expression of MMP-9 was reduced(P＜0.01)and the ratio MMP-9/TIMP-1 was regulated to balance in control group with C.
【CONCLUSION】pulmonary surfactant may down-regulate the expression ofMMP-9 and modulate the equilibration of the ratio of MMP-9/TIMP-1,supressinflammatory reaction ,protect pulmonary and delay progress in COPD.pulmonary surfactant may have a protective and therapeutic effect on COPDmodel of rats by alleviating airway inflammatory reaction, decreasing the destructionof alveolar and improving the lung function.
方法30只健康雄性Wistar大鼠随机分为三个实验组：健康对照组(n=10)、COPD模型组(n=10)和PS干预组(n=10)。健康对照组：正常喂养，不做任何干预；COPD模型组：采用香烟熏吸加气道内注入脂多糖法建立大鼠COPD模型，并于实验第2、3、5、6周行假手术做为对照；PS干预组建立模型方法同COPD模型组，但于实验第2、3、5、6周给予气管内注入外源性PS。6周后，检测各组动物的肺功能、动脉血气；光镜观察肺组织病理学改变并应用显微—微机图像分析系统进行形态学定量检测；应用免疫组化方法检测基质金属蛋白酶9及金属基质蛋白酶组织抑制剂(TIMP-1)的阳性表达。
结果该法建立被动吸烟致肺损伤大鼠模型的肺组织病理学改变基本符合人类COPD组织病理学改变特点。大鼠肺功能检测结果：COPD模型组呼气阻力(Re)、FEV_(0.3)、FEV_(0.3)／FVC与健康对照组比较有显著性差异(P＜0.01)；与PS干预组比较有显著性差异(P＜0.01)；PS干预组与健康对照组比较，FEV_(0.3)／FVC差别有统计学意义(P＜0.05)，Re及FVE_(0.3)比较无显著性差异(P＞0.05)。动脉血气结果：COPD模型组PaO_2、PaCO_2与健康对照组比较有显著性差异(P＜0.01)；与PS干预组比较有显著性差异(P＜0.05)；PS干预组与健康对照组比较，PaO_2、PaCO_2差别有统计学意义(P＜0.05)。肺组织病理学改变：COPD模型组肺平均内衬间隔(MLI)、平均肺泡数(MAN)、肺泡气腔与肺总面积比(PAA)％]与健康对照组比较有显著性差异(P＜0.01)；与PS干预组比较有显著性差异(P＜0.01)；健康对照组MLI、PAA与PS干预组比较有显著性差异(P＜0.01)。COPD模型组MMP-9、TIMP-1表达增强，二者相对阳性面积及MMP-9／TIMP1与健康对照组比较有显著性差异(P＜0.01)，与PS干预组比较有显著性差异(P＜0.01)，PS干预组MMP-9、TIMP-1表达与健康对照组比较仍增强有显著性差异(P＜0.01)，但MMP-9／TIMP1与健康对照组比较无显著性差异
结论被动吸烟及气管内注入脂多糖可引起肺部损伤，导致肺功能下降，血气指标发生改变，肺组织发生损伤，MMP-9，TIMP-1表达增强，MMP-9／TIMP-1比例失衡。应用外源性PS进行干预可对COPD大鼠的气道炎症有明显的抑制作用，减轻肺组织的损伤，MMP-9表达减少，MMP-9／TIMP-1比例趋于平衡，并改善肺功能，对COPD的发生起到预防保护作用，延缓病情发展。
【OBJECTIVE】To investigate the expression of matrix metalloproteinases-9(MMP-9)and his tissue inhibitor (TIMP-1) in the lung of smoke-induced chronic obstructivepulmonary disease(COPD) in rats and the therapeutic effect of pulmonary surfactant.
【METHODS】COPD animal model was established by smoke inhalations andintratracheal instillations of lipopolysaccharide in Wistar rats. Thirty Wistar ratswere randomly divided into 3 groups as follows: normal group(N), controlgroup(C),and treatment group(T).The last two groups received smoke inhalationsdaily for 6 weeks and received intratracheal instillations of lipopolysaccharide twice,one of which received exogenous pulmonary surfactant treatment(100mg/Kg BW) inthe 2nd,3rd,5th,6th week(4 times) by intratracheal instillation before exposure tocigarette smoking. Lung function test、blood gas analysis、light microscopyobservations were performed in each group. Pulmonary mean linear intercept (MLI),mean alveolar numbers (MAN), and pulmonary alveolar area (PAA) was measured byimage analysis. The expression of MMP-9 and TIMP-1 were observed byimmunohistochemistry.
【RESULTS】Smoking for 6 weeks and instillations of lipopolysaccharide twiceresulted in chronic bronchitis and emphysema(Fig 2,5). MLI and PAA increased andMAN decreased in the two experimental groups compared with in the normal group(P＜0.01)(table 1).FEV_(0.3) and FEV_(0.3)/FVC decreased and Re increased in the twoexperiment groups compared with in the normal group (P＜0.01)(table 2).PaO_2decreased and PaCO_2 increased in the two experimental groups compared with in thenormal group(table 3). Administration of exogenous pulmonary surfactant for 4times resulted in statistically significant inhibition of pulmonary injury (Fig 3, 6).MLI and PAA decreased and MAN increased in T compared with in C(P＜0.01).Thelung function was improved in T compared with in C(P＜0.01): FEV_(0.3) andFEV_(0.3)/FVC increased and Re decreased in T, also the PaO_2 increased and PaCO_2decreased. The expresstion of MMP-9 increased significantly (P＜0.01) and the ratioMMP-9/TIMP-1 was unbalance in model group (Fig8、11) with N(Fig7、10).Administration of exogenous pulmonary surfactant for 4 times resulted in statisticallysignificant inhibition of pulmonary injury. The expression of MMP-9 was reduced(P＜0.01)and the ratio MMP-9/TIMP-1 was regulated to balance in control group with C.
【CONCLUSION】pulmonary surfactant may down-regulate the expression ofMMP-9 and modulate the equilibration of the ratio of MMP-9/TIMP-1,supressinflammatory reaction ,protect pulmonary and delay progress in COPD.pulmonary surfactant may have a protective and therapeutic effect on COPDmodel of rats by alleviating airway inflammatory reaction, decreasing the destructionof alveolar and improving the lung function.
引文
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[1] 程显声，徐希胜，张珍祥，等慢性阻塞性肺疾病、肺心病社区人群综合干预结果[J] 中华结核和呼吸杂志，2001，24(10)：579-583
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