化纤汤对肺纤维化大鼠肺组织细胞外基质代谢的干预作用及机制
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摘要
目的肺纤维化的发病率有逐年增高趋势，然而由于其病因和发病机制尚未阐明，迄今尚无特效疗法，病死率高，成为严重威胁人类健康的难治性疾病。临床表明，中医药治疗不仅能有效改善症状，提高患者的生存质量，而且可以极大降低本病的死亡率，因此，总结和探讨肺间质纤维化的中医药治疗具有很大的必要性和现实意义。化纤汤是根据肺间质纤维化的基本病机特点所拟定的基本方，以益气通阳、行气活血化痰为治法，在临床上以该方为基本方治疗各期肺间质纤维化取得显著疗效。本课题以博莱霉素诱导的大鼠肺纤维化为模型，以影响细胞外基质代谢的细胞因子和基质金属蛋白酶系统为主要切入点，观察化纤汤对肺组织病理形态和超微结构的影响、对基质金属蛋白酶及其组织抑制剂表达的影响、细胞因子PDGF、TGFβ1含量的影响以及肺组织HYP含量的影响来进行研究，目的是通过动物实验，验证和客观评价化纤汤的疗效，并探究其可能的作用途径和机制。
方法144只健康Wistar大鼠，体重200±20g，随机分为六组：正常对照组、模型对照组、强的松组、中药大剂量组、中剂量组和小剂量组，每组24只。除正常对照组外，其他五组均采用经气管滴注博莱霉素(BLM)建立大鼠肺纤维化模型，造模后第二日起化纤汤大、中、小剂量组每天用化纤汤(2g／ml、1g／ml、0.5g／ml)灌胃，强的松组用醋酸强的松混悬液(0.32mg／ml)灌胃，正常对照组与模型组生理盐水灌胃，每日一次，剂量为10ml／kg·bw。每组分别于第7、14和28天随机处死8只，HE染色及光镜、电镜观察大鼠肺组织显微及超微结构的病理形态学变化；观察大鼠肺系数变化；运用免疫组织化学分析法检测大鼠肺组织MMP-9及TIMP-1表达的变化；运用ELISA法检测大鼠血清中细胞因子PDGF及TGFβ1含量的变化；运用样本碱水解法检测肺组织羟脯氨酸含量的变化；运用RT-PCR法观察大鼠肺组织MMP-2mRNA表达的变化；以及化纤汤对上述各项指标的影响。
结果(1)化纤汤可明显降低实验性肺纤维化大鼠肺系数(P＜0.01)，化纤汤大剂量组作用优于小剂量组(P＜0.05)，强的松组、化纤汤大、中剂量组三组间差异无显著性意义(P＞0.05)；肺组织病理形态光镜和超微结构的电镜观察表明，强的松组、化纤汤大、中、小剂量组与模型组相比病理改变均有不同程度改善，各组间肺泡炎的差异具有显著性(P＜0.01或0.05)，由重到轻排序为模型组，化纤汤小剂量组，化纤汤中剂量组，强的松组，化纤汤大剂量组，正常组；各组间肺纤维化的差异具有显著性(P＜0.01或0.05)，纤维化程度排序由重到轻依次为模型组，强的松组，化纤汤小剂量组，化纤汤中剂量组，化纤汤大剂量组，正常对照组；(2)与正常对照组比较，模型对照组大鼠第7、14、28天时肺组织中MMP-9、TIMP-1阳性细胞率均明显升高(P＜0.01)，与模型对照组大鼠相比，强的松组、化纤汤大、中、小剂量组肺组织中MMP-9、TIMP-1阳性细胞率均明显降低(P＜0.01或0.05)，组间比较发现，在三个时间点化纤汤大剂量组MMP-9阳性细胞率与强的松组无显著差异(P＞0.05)，但与中、小剂量组相比差异显著(P＜0.05)；TIMP-1阳性细胞率第7天时，强的松组、化纤汤大、中、小剂量组间无显著性差异(P＞0.05)，第14天时，大剂量组与小剂量组间有显著性差异(P＜0.05)，第28天时，大、中剂量组间差异无显著性(P＞0.05)，但均明显低于小剂量组(P＜0.05)；(3)与正常对照组相比，模型对照组PDGF、TGFβ1含量在各时间点均显著增加(P＜0.01)，强的松组、化纤汤大、中、小剂量组在各时间点上PDGF、TGFβ1的含量比正常对照组明显增加(P＜0.01)，但显著低于模型对照组(P＜0.01)，化纤汤各组间比较，各时间点大、小剂量组间PDGF含量的差异具有显著意义(P＜0.05)；第7天时，大、小剂量组间TGFβ1含量的差异具有显著意义(P＜0.05)，第14天和第28天时，大剂量组与中、小剂量组TGFβ1含量的差异均具有显著意义(P＜0.05)；(4)与正常对照组比较，模型对照组各时间点肺组织羟脯氨酸含量均明显升高，特别是在第28天达到高峰，在各时间点上，强的松组和化纤汤各组HYP含量均明显高于正常对照组(P＜0.01)，但显著低于同期模型对照组(P＜0.01)，组间比较，第7、14天时化纤汤各组间差异无显著意义(P＞0.05)，第28天时，化纤汤大剂量组与小剂量组比较具有显著差异(P＜0.05)；(5)各实验组在第7天、第14天、第28天三个时间点均有MMP-2mRNA的表达，与正常对照组相比，模型对照组第7天含量显著升高(P＜0.01)，第14天时达到高峰，第28天虽较第7、14天时有所降低，但仍明显高于同期正常对照组(P＜0.01)，与模型对照组比较，强的松和化纤汤各组各时间点含量均明显降低(P＜0.01)，化纤汤各组间比较，大剂量组在三个时间点MMP-2mRNA的表达均明显低于小剂量组(P＜0.05)。
结论化纤汤对博莱霉素诱导的大鼠肺纤维化具有一定的防治作用，这一作用可能是通过以下途径实现的：降低肺组织MMP-9、TIMP-1的表达，调节MMP-9／TIMP-1系统，使之趋于平衡；降低PDGF、TGFβ1含量；减少肺组织中羟脯氨酸的沉积；降低肺组织中MMP-2mRNA的表达。化纤汤从多靶点、多环节纠正细胞外基质的过度沉积，有效保护肺组织的正常形态，对肺纤维化的发生和发展起到一定的防治作用。
Objective Pulmonary fibrosis is a hardly treated disease which seriously threatens human health with increasing incidence and high death rate. The therapeutic approach to this disease is not particularly effective in western medicine because of its unclear pathogenesis and mechanism. Traditional Chinese medicine has reached a several achievements in improving symptoms and reducing death rate, and it is necessary to summarize and improve the methods of TCM for this disease. Huaxian decoction (HD), a composite recipe of tonifying qi and regulating yang, smoothing qi invigorating blood and eliminating sputum, has shown a bright future in clinical study. In this study, we extensively investigate the effects of HD on the expression of MMP-9、TIMP-1、MMP-2、HYP、PDGF、TGFβ1 in pulmonary fibrosis rats induced by blyomicin to evaluate its curative effect objectively and explore its probable way and mechanism.
Methods One hundred and forty-four healthy Wistar rats weighted from 180 to 220 grams were randomly divided into six groups(n=24, each): normal control group, model group, prednisone group, HD groups of high, moderate and low dosage. The rat model was induced by bleomycin and respective medicine was given to each group. Every group was subdivided into three groups (n=8) which was killed in the 7th, 14th and 28th day respectively. The rat's lung tissue section was observed under light microscope and electron microscope to study the alternation of pathological morphology; the pulmonary coefficients were observed respectively; the expressions of MMP-9 and TIMP-1 were detected with immunohistochemical method of analysis; the expressions of PDGF、TGFβ1 were assayed with ELISA method; the contents of HYP were measured with method of specimen alkali hydrolysis; the expressions of MMP-2mRNA were studied with RT-PCR method; and effects on above items of HD were observed.
Results (1)HD may significantly reduce the pulmonary coefficients of rats with pulmonary fibrosis induced by bleomycin (P＜0.01). There was significant difference between HD high and low dosage group (P＜0.05). Changes of pathologic morphogenesis under light microscope and electron microscope had shown improvement in prednisone group and HD groups. There were significant differences among groups in Szapiel grade of alveolitis and fibrosis (P＜0.01 or 0.05). The pathologic change of alveolitis from the most obviously to the most slightly was model group, HD low dosage group, HD moderate dosage group, prednisone group, HD high dosage group, normal control group, while that of fibrosis was model group, prednisone group, HD low dosage group, HD moderate dosage group, HD high dosage group, normal control group. (2) In the 7th、14th and 28th day, percentage of positively reaction cell of MMP-9、TIMP-1 was markedly higher in model group than in normal control group (P＜0.01), and it was also markedly higher than in prednisone group and HD groups (P＜0.01 or 0.05), which were significantly higher than normal control group. (3)Contents of PDGF and TGFβ1 in each phases in model group were significantly higher than in normal control group respectively (P＜0.01). Those in prednisone group and HD groups were much lower than in model group (P＜0.01), but those were higher than in normal control group (P＜0.01). (4) Contents of HYP in model group were higher than in normal control group(P＜0.01 )in each phase respectively, and they reached their peak in the 28th day. In prednisone group and HD groups, those were markedly lower than in model group (P＜0.01), though those were higher than in normal control group (P＜0.01). (5) Expression of MMP-2mRNA could be observed in each group in each time. It was obviously higher at the 7th day in model group than in normal control group (P＜0.01), and it reached its peak in the 14th day. In the 28th day, it was still markedly higher than in normal control group (P＜0.01). In prednisone group and HD groups, it was obviously lower than in model group (P＜0.01).
Conclusion MMP-9、TIMP-1、MMP-2、HYP、PDGF and TGFβ1 may play important roles in the course of rat pulmonary fibrosis induced by bleomycin. HD can prevent and treat pulmonary fibrosis. This effect could be carried out by following ways: Reduce expression of MMP-9 and TIMP-1 in pulmonary tissue and adjust the system of MMP-9/TIMP-1 to reach its equilibrium; Decrease content of PDGF and TGFβ1; Restrain HYP from over-depositing in the pulmonary tissue; Reduce the expression of MMP-2mRNA in the pulmonary tissue. HD may adjust over-depositing of extra cellular matrix in the pulmonary tissue and protect the normal pulmonary morphogenesis with poly-link and poly-target, so as to play an active role in preventing and treating pulmonary fibrosis.
方法144只健康Wistar大鼠，体重200±20g，随机分为六组：正常对照组、模型对照组、强的松组、中药大剂量组、中剂量组和小剂量组，每组24只。除正常对照组外，其他五组均采用经气管滴注博莱霉素(BLM)建立大鼠肺纤维化模型，造模后第二日起化纤汤大、中、小剂量组每天用化纤汤(2g／ml、1g／ml、0.5g／ml)灌胃，强的松组用醋酸强的松混悬液(0.32mg／ml)灌胃，正常对照组与模型组生理盐水灌胃，每日一次，剂量为10ml／kg·bw。每组分别于第7、14和28天随机处死8只，HE染色及光镜、电镜观察大鼠肺组织显微及超微结构的病理形态学变化；观察大鼠肺系数变化；运用免疫组织化学分析法检测大鼠肺组织MMP-9及TIMP-1表达的变化；运用ELISA法检测大鼠血清中细胞因子PDGF及TGFβ1含量的变化；运用样本碱水解法检测肺组织羟脯氨酸含量的变化；运用RT-PCR法观察大鼠肺组织MMP-2mRNA表达的变化；以及化纤汤对上述各项指标的影响。
结果(1)化纤汤可明显降低实验性肺纤维化大鼠肺系数(P＜0.01)，化纤汤大剂量组作用优于小剂量组(P＜0.05)，强的松组、化纤汤大、中剂量组三组间差异无显著性意义(P＞0.05)；肺组织病理形态光镜和超微结构的电镜观察表明，强的松组、化纤汤大、中、小剂量组与模型组相比病理改变均有不同程度改善，各组间肺泡炎的差异具有显著性(P＜0.01或0.05)，由重到轻排序为模型组，化纤汤小剂量组，化纤汤中剂量组，强的松组，化纤汤大剂量组，正常组；各组间肺纤维化的差异具有显著性(P＜0.01或0.05)，纤维化程度排序由重到轻依次为模型组，强的松组，化纤汤小剂量组，化纤汤中剂量组，化纤汤大剂量组，正常对照组；(2)与正常对照组比较，模型对照组大鼠第7、14、28天时肺组织中MMP-9、TIMP-1阳性细胞率均明显升高(P＜0.01)，与模型对照组大鼠相比，强的松组、化纤汤大、中、小剂量组肺组织中MMP-9、TIMP-1阳性细胞率均明显降低(P＜0.01或0.05)，组间比较发现，在三个时间点化纤汤大剂量组MMP-9阳性细胞率与强的松组无显著差异(P＞0.05)，但与中、小剂量组相比差异显著(P＜0.05)；TIMP-1阳性细胞率第7天时，强的松组、化纤汤大、中、小剂量组间无显著性差异(P＞0.05)，第14天时，大剂量组与小剂量组间有显著性差异(P＜0.05)，第28天时，大、中剂量组间差异无显著性(P＞0.05)，但均明显低于小剂量组(P＜0.05)；(3)与正常对照组相比，模型对照组PDGF、TGFβ1含量在各时间点均显著增加(P＜0.01)，强的松组、化纤汤大、中、小剂量组在各时间点上PDGF、TGFβ1的含量比正常对照组明显增加(P＜0.01)，但显著低于模型对照组(P＜0.01)，化纤汤各组间比较，各时间点大、小剂量组间PDGF含量的差异具有显著意义(P＜0.05)；第7天时，大、小剂量组间TGFβ1含量的差异具有显著意义(P＜0.05)，第14天和第28天时，大剂量组与中、小剂量组TGFβ1含量的差异均具有显著意义(P＜0.05)；(4)与正常对照组比较，模型对照组各时间点肺组织羟脯氨酸含量均明显升高，特别是在第28天达到高峰，在各时间点上，强的松组和化纤汤各组HYP含量均明显高于正常对照组(P＜0.01)，但显著低于同期模型对照组(P＜0.01)，组间比较，第7、14天时化纤汤各组间差异无显著意义(P＞0.05)，第28天时，化纤汤大剂量组与小剂量组比较具有显著差异(P＜0.05)；(5)各实验组在第7天、第14天、第28天三个时间点均有MMP-2mRNA的表达，与正常对照组相比，模型对照组第7天含量显著升高(P＜0.01)，第14天时达到高峰，第28天虽较第7、14天时有所降低，但仍明显高于同期正常对照组(P＜0.01)，与模型对照组比较，强的松和化纤汤各组各时间点含量均明显降低(P＜0.01)，化纤汤各组间比较，大剂量组在三个时间点MMP-2mRNA的表达均明显低于小剂量组(P＜0.05)。
结论化纤汤对博莱霉素诱导的大鼠肺纤维化具有一定的防治作用，这一作用可能是通过以下途径实现的：降低肺组织MMP-9、TIMP-1的表达，调节MMP-9／TIMP-1系统，使之趋于平衡；降低PDGF、TGFβ1含量；减少肺组织中羟脯氨酸的沉积；降低肺组织中MMP-2mRNA的表达。化纤汤从多靶点、多环节纠正细胞外基质的过度沉积，有效保护肺组织的正常形态，对肺纤维化的发生和发展起到一定的防治作用。
Objective Pulmonary fibrosis is a hardly treated disease which seriously threatens human health with increasing incidence and high death rate. The therapeutic approach to this disease is not particularly effective in western medicine because of its unclear pathogenesis and mechanism. Traditional Chinese medicine has reached a several achievements in improving symptoms and reducing death rate, and it is necessary to summarize and improve the methods of TCM for this disease. Huaxian decoction (HD), a composite recipe of tonifying qi and regulating yang, smoothing qi invigorating blood and eliminating sputum, has shown a bright future in clinical study. In this study, we extensively investigate the effects of HD on the expression of MMP-9、TIMP-1、MMP-2、HYP、PDGF、TGFβ1 in pulmonary fibrosis rats induced by blyomicin to evaluate its curative effect objectively and explore its probable way and mechanism.
Methods One hundred and forty-four healthy Wistar rats weighted from 180 to 220 grams were randomly divided into six groups(n=24, each): normal control group, model group, prednisone group, HD groups of high, moderate and low dosage. The rat model was induced by bleomycin and respective medicine was given to each group. Every group was subdivided into three groups (n=8) which was killed in the 7th, 14th and 28th day respectively. The rat's lung tissue section was observed under light microscope and electron microscope to study the alternation of pathological morphology; the pulmonary coefficients were observed respectively; the expressions of MMP-9 and TIMP-1 were detected with immunohistochemical method of analysis; the expressions of PDGF、TGFβ1 were assayed with ELISA method; the contents of HYP were measured with method of specimen alkali hydrolysis; the expressions of MMP-2mRNA were studied with RT-PCR method; and effects on above items of HD were observed.
Results (1)HD may significantly reduce the pulmonary coefficients of rats with pulmonary fibrosis induced by bleomycin (P＜0.01). There was significant difference between HD high and low dosage group (P＜0.05). Changes of pathologic morphogenesis under light microscope and electron microscope had shown improvement in prednisone group and HD groups. There were significant differences among groups in Szapiel grade of alveolitis and fibrosis (P＜0.01 or 0.05). The pathologic change of alveolitis from the most obviously to the most slightly was model group, HD low dosage group, HD moderate dosage group, prednisone group, HD high dosage group, normal control group, while that of fibrosis was model group, prednisone group, HD low dosage group, HD moderate dosage group, HD high dosage group, normal control group. (2) In the 7th、14th and 28th day, percentage of positively reaction cell of MMP-9、TIMP-1 was markedly higher in model group than in normal control group (P＜0.01), and it was also markedly higher than in prednisone group and HD groups (P＜0.01 or 0.05), which were significantly higher than normal control group. (3)Contents of PDGF and TGFβ1 in each phases in model group were significantly higher than in normal control group respectively (P＜0.01). Those in prednisone group and HD groups were much lower than in model group (P＜0.01), but those were higher than in normal control group (P＜0.01). (4) Contents of HYP in model group were higher than in normal control group(P＜0.01 )in each phase respectively, and they reached their peak in the 28th day. In prednisone group and HD groups, those were markedly lower than in model group (P＜0.01), though those were higher than in normal control group (P＜0.01). (5) Expression of MMP-2mRNA could be observed in each group in each time. It was obviously higher at the 7th day in model group than in normal control group (P＜0.01), and it reached its peak in the 14th day. In the 28th day, it was still markedly higher than in normal control group (P＜0.01). In prednisone group and HD groups, it was obviously lower than in model group (P＜0.01).
Conclusion MMP-9、TIMP-1、MMP-2、HYP、PDGF and TGFβ1 may play important roles in the course of rat pulmonary fibrosis induced by bleomycin. HD can prevent and treat pulmonary fibrosis. This effect could be carried out by following ways: Reduce expression of MMP-9 and TIMP-1 in pulmonary tissue and adjust the system of MMP-9/TIMP-1 to reach its equilibrium; Decrease content of PDGF and TGFβ1; Restrain HYP from over-depositing in the pulmonary tissue; Reduce the expression of MMP-2mRNA in the pulmonary tissue. HD may adjust over-depositing of extra cellular matrix in the pulmonary tissue and protect the normal pulmonary morphogenesis with poly-link and poly-target, so as to play an active role in preventing and treating pulmonary fibrosis.
引文
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