Inducible lung-specific urokinase expression reduces fibrosis and mortality after lung injury in mice.
Inducible lung-specific urokinase expression reduces fibrosis and mortality after lung injury in mice.
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诱导性肺特异性尿激酶表达可减少小鼠肺损伤后的纤维化和死亡率。
DOI：
10.1152/ajplung.00049.2002
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Simon,RichardH
中科院分区：
文献类型：
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作者：
Sisson,ThomasH;Hanson,KerstinE;Subbotina,Natalya;Patwardhan,Anjali;Hattori,Noboru;Simon,RichardH
纤溶酶原激活物抑制剂-1（派-1）缺陷型转基因小鼠经皮内滴注博来霉素后存活率提高，纤维化程度降低。我们推测派-1缺乏通过无对抗性纤溶酶原激活限制瘢痕形成。如果这是真的，那么我们可以预期增加尿激酶型纤溶酶原激活剂（uPA）的表达，导致类似的减少瘢痕和改善死亡率。为了验证我们的假设，使用四环素基因调控系统，我们已经产生了一个转基因小鼠模型的诱导，肺特异性uPA生产的功能。多西环素给药后，这些转基因动物的支气管肺泡灌洗液（BAL）中uPA水平升高，加速了肺内纤维蛋白的清除。重要的是，这种增加的纤溶酶原激活物产生导致博来霉素诱导的损伤后肺胶原积聚和死亡率降低。这些结果表明，派-1缺陷确实通过无对抗性纤溶酶生成来保护博莱霉素诱导的肺损伤。通过允许在纤维化过程的不同阶段操纵纤溶酶原活化，该模型将作为进一步研究肺纤维化发病机制的有力工具。
Plasminogen activator inhibitor-1 (PAI-1)-deficient transgenic mice have improved survival and less fibrosis after intratracheal bleomycin instillation. We hypothesize that PAI-1 deficiency limits scarring through unopposed plasminogen activation. If this is indeed true, then we would expect increased urokinase-type plasminogen activator (uPA) expression to result in a similar reduction in scarring and improvement in mortality. To test our hypothesis, using the tetracycline gene regulatory system, we have generated a transgenic mouse model with the features of inducible, lung-specific uPA production. After doxycycline administration, these transgenic animals expressed increased levels of uPA in their bronchoalveolar lavage (BAL) fluid that accelerated intrapulmonary fibrin clearance. Importantly, this increased plasminogen activator production led to a reduction in both lung collagen accumulation and mortality after bleomycin-induced injury. These results suggest that PAI-1 deficiency does protect against the effects of bleomycin-induced lung injury through unopposed plasmin generation. By allowing the manipulation of plasminogen activation at different phases of the fibrotic process, this model will serve as a powerful tool in further investigations into the pathogenesis of pulmonary fibrosis.