The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system.
The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system.
复制标题
缺乏纤溶系统成分的小鼠中博来霉素诱导的肺纤维化的发展。
DOI：
10.1016/s0002-9440(10)64529-4
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Ploplis,VA
中科院分区：
文献类型：
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作者：
Swaisgood,CM;French,EL;Noga,C;Simon,RH;Ploplis,VA
急性和慢性肺部疾病的特征是肺内纤维蛋白溶解活性受损。为了确定纤溶系统在调节与肺损伤相关的病理中的作用，我们在缺乏纤溶酶原（Pg−/−）、尿激酶（u-PA−/−）、尿激酶受体（u-PAR−/−）或组织纤溶酶原激活剂（t-PA−/−）的小鼠和对照野生型（WT）小鼠中检测了博来霉素的作用。博来霉素是一种诱导肺纤维化发展的药物。与WT小鼠相比，Pg−/−和t-PA−/−小鼠的肺胶原含量增加。u-PA−/−和u-PAR−/−小鼠的水平与WT小鼠相似。肺损伤后14天的组织学分析证实，相对于WT和u-PAR - / -小鼠，Pg−/ -、u-PA−/ -和t-PA−/ -小鼠间质纤维化增强。在博莱霉素处理的WT小鼠中观察到肺出血区域，而在Pg−/−、u-PA−/−和u-PAR−/−小鼠或生理盐水对照组中未观察到肺出血区域。相反，博莱霉素治疗的Pg - / -和u-PA - / -小鼠的肺部出现了广泛的纤维化区域。在t-PA−/−和Pg+/−小鼠中观察到混合表型（出血和纤维化）。含铁血黄素的巨噬细胞在出血小鼠的肺中大量存在，这些小鼠容易早期死亡。在出血表型小鼠中发现肺中巨噬细胞水平增强和基质金属弹性酶（MMP-12）的激活。这些研究结果表明纤维蛋白溶解系统在急性肺损伤中的作用，并表明肺泡内出血是基底膜降解的结果，通过细胞介导的u-PA活化Pg，可能参与基质金属蛋白酶。缺少这两种纤溶系统的组成部分，无论是尿激酶还是纤溶酶原，都会导致纤维化加速。
Acute and chronic pulmonary diseases are characterized by impaired fibrinolytic activity within the lung. To determine the role of the fibrinolytic system in regulating the pathologies associated with lung injury, we examined the effect of bleomycin, an agent that induces the development of pulmonary fibrosis, in mice deficient for plasminogen (Pg−/−), urokinase (u-PA−/−), urokinase receptor (u-PAR−/−), or tissue plasminogen activator (t-PA−/−), and in control wild-type (WT) mice. Pg−/−and t-PA−/−mice demonstrated an enhanced increase in lung collagen content relative to that observed in WT mice. Levels in u-PA−/−and u-PAR−/−mice were similar to those in WT mice. Histological analysis 14 days after lung injury confirmed enhanced interstitial fibrosis in Pg−/−, u-PA−/−, and t-PA−/−mice relative to WT and u-PAR−/−mice. Areas of pulmonary hemorrhage were observed in bleomycin-treated WT mice and not in Pg−/−, u-PA−/−, and u-PAR−/−mice or saline controls. Instead, extensive areas of fibrosis were present throughout the lungs of bleomycin-treated Pg−/−and u-PA−/−mice. A mixed phenotype (hemorrhage and fibrosis) was observed in t-PA−/−and Pg+/−mice. Hemosiderin-laden macrophages were abundant in the lungs of mice exhibiting hemorrhage and these mice were prone to an early death. Enhanced macrophage levels in the lungs and activation of matrix metalloelastase (MMP-12) were found in mice with a hemorrhage phenotype. The results of these studies indicate a role for the fibrinolytic system in acute lung injury and suggests that intra-alveolar hemorrhage is the result of basement membrane degradation through cell-mediated u-PA activation of Pg with possible involvement of matrix metalloproteinases. Absence of these two components of the fibrinolytic system, either urokinase or plasminogen, results in accelerated fibrosis.