纤溶异常在慢性阻塞性肺病早期缺氧大鼠肺纤维化中的作用

Effect of abnormal fibrinolysis on early hypoxia-induced pulmonary fibrosis in rats

目的探讨慢性阻塞性肺病（COPD）早期缺氧时纤溶异常与肺纤维化的关系。方法将70只雄性SD大鼠随机分为无缺氧对照组（10只）、COPD缺氧1个月组（一月组，20只）、COPD缺氧2个月组（二月组，20只）及COPD缺氧3个月组（三月组，20只）。模型建立成功后各组大鼠行肺功能测定，处死后肺组织作病理切片，并以HE染色及免疫组化法检测肺组织I、Ⅲ型胶原的表达情况；采用ELISA法测定大鼠肺泡灌洗液（BALF）及血浆中抗凝血酶Ⅲ（AT-Ⅲ）和纤溶酶原激活物抑制剂（PAI-1）的浓度。结果COPD缺氧各组大鼠均形成明显的肺泡炎和肺间质纤维化，并随着缺氧时间延长逐渐加重。与对照组比较，其它三组大鼠I型胶原的表达均明显增强（P〈005）、一月组和二月组Ⅲ型胶原的表达均明显增强（P〈0．05）、三月组Ⅲ型胶原的表达均明显降低（P〈0．05）；与一月组比较。二月组及三月组I型胶原表达均明显增强（P〈0．05）、三月组Ⅲ胶原表达明显降低（P〈0．05）；与二月组比较，三月组I型胶原的表达明显增强（P〈0．05）、Ⅲ型胶原的表达均明显降低（P〈0．05）；三月组I/Ⅲ胶原表达比值较之其它各组均明显增大（P〈0．05）。模型组大鼠BALF及血浆中AT－Ⅲ浓度均较对照组明显降低（均P〈0．05），二月组及三月组PAI－1浓度均较对照组明显升高（均P〈0.05）；二月组及三月组BALF中PAI－1浓度均较一月组明显升高（均P〈0．05）；三月组BALF中PAI－1浓度较二月组亦明显升高（P〈0.05）。结论COPD早期缺氧所致纤溶异常在肺纤维化的发病过程中起着一定的作用；缺氧时间越长，AT－Ⅲ产生越少，PAI－1合成增多，进而引起肺泡内纤维蛋白形成的增加和清除障碍，这种失衡促进了肺间质纤维化的发生。

Objective To investigate the effect of abnormal fibrinolysis on early hypoxia-induced pulmonary fibrosis in rats. Methods Seventy male rats were randomly divided into four groups： control group （no hypoxia, n=20）, chronic obstructive pulmonary disease （COPD） hypoxia one month group （1M group, n=20 ）, COPD hypoxia two months group （2M group, n=20） and COPD hypoxia three months group （ 3M group,20 rats ）. The lung function tests were performed in each group; collagen I and III in rat lungs were determined by immunohistochemistry staining; antithrombin III （AT- III ） and plasminogen activator inhibitor （PAI-1） in bronchoalveolar lavage fluid （BALF） and blood were determined by ELISA. Results Evident airsacculitis and pulmonary interstitial fibrosis emerged in all hypoxia groups, and the severity was increased with the time of hypoxia. Compared to control group, collagen I in lung increased remarkably in hypoxia group （P〈0.05）. Collagen III was also increased in 1M and 2M groups （P〈0.05）; however, decreased in 3M group （P〈0.05）. Compared to tM group, collagen I in lung increased remarkably in 2M and 3M groups （P〈0.05）, collagen III decreased in 3M group （P〈0.05）. Compared to 2M group, collagen I increased and collagen lU decreased in 3M group （P〈0.05）. Compared to other groups, the collage I / III ratio markedly increased in 3M group （P〈0.05）. ELISA tests showed that AT- III significantly decreased in BALF and plasma in hypoxia groups than those in the control group （P〈0.05）. However, PAl-1 concentration in 2M group and 3M group increased than those in control group （P〈0.05）. Compared to 1M group, PAl-1 concentration in BALF increased remarkably in 2M and 3M groups （P〈0.05）. Compared to 2M group, PAl-1 concentration in BALF significantly increased in 3M group （P〈0.05）. Conclusion Fibrinolytic abnormalities induced by early hypoxia may play an important role in lung collagen production and the pathogenesis of pulmonary fibrosis.