Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene
Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene
复制标题
DOI：
10.1172/jci118396
复制
发表时间：
1996-01-01
影响因子：
15.9
通讯作者：
Simon, RH
中科院分区：
文献类型：
--
作者：
Eitzman, DT;McCoy, RD;Simon, RH
肺内纤溶活性受损是急性和慢性炎症性肺病的常见表现，因为纤溶系统在将受损组织恢复正常的修复过程中是活跃的，纤溶活性降低可能有助于肺纤维化的后续发展。为了检测纤溶系统和肺纤维化之间的关系，在过表达或完全缺乏鼠纤溶酶原激活物抑制剂-1（派-1）的转基因小鼠中，在0.075 U博莱霉素后2周，PAI-I过表达的转基因小鼠肺组织中羟脯氨酸含量显著增加，（118 +/- 8 μ g）比同窝对照组（70.5 +/- 8 μ g，P < 0.005），给予较高剂量博来霉素后3周（0.15 U），派-1完全缺失小鼠肺组织羟脯氨酸含量（49 +/- 8 μ g）无显著差异（P = 0.63）比接受生理盐水的对照动物（37 ± 1 μ g），而杂合子中羟脯氨酸含量显著增加（77 +/- 12 μ g，P = 0.06）和野生型（124 +/- 19 μ g，P < 0.001）同窝出生的小鼠。这些数据表明派-1表达的基因决定水平和炎症性肺损伤后胶原蛋白积聚的程度之间存在直接相关性。这些结果强烈支持纤溶活性的改变影响炎症性损伤后发生的肺纤维化程度的假设。
Impaired fibrinolytic activity within the lung is a common manifestation of acute and chronic inflammatory lung diseases, Because the fibrinolytic system is active during repair processes that restore injured tissues to normal, reduced fibrinolytic activity may contribute to the subsequent development of pulmonary fibrosis. To examine the relationship between the fibrinolytic system and pulmonary fibrosis, lung inflammation was induced by bleomycin in transgenic mice that either overexpressed or were completely deficient in murine plasminogen activator inhibitor-1 (PAI-1), 2 wk after 0.075 U of bleomycin, the lungs of transgenic mice overexpressing PAI-I contained significantly more hydroxy-proline (118 +/- 8 mu g) than littermate controls (70.5 +/- 8 mu g, P < 0.005), 3 wk after administration of a higher dose of bleomycin (0.15 U), the lung hydroxyproline content of mice completely deficient in PAI-1 (49 +/- 8 mu g) was not significantly different (P = 0.63) than that of control animals receiving saline (37 +/- 1 mu g), while hydroxyproline content was significantly increased in heterozygote (77 +/- 12 mu g, P = 0.06) and wild-type (124 +/- 19 mu g, P < 0.001) littermates. These data demonstrate a direct correlation between the genetically determined level of PAI-1 expression and the extent of collagen accumulation that follows inflammatory lung injury, These results strongly support the hypothesis that alterations in fibrinolytic activity influence the extent of pulmonary fibrosis that occurs after inflammatory injury.