The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism
The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism
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DOI：
10.1016/s0002-9440(10)63196-3
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发表时间：
2004-03-01
影响因子：
6
通讯作者：
Miyake, M
中科院分区：
文献类型：
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作者：
Hattori, N;Mizuno, S;Miyake, M
纤溶酶原激活物抑制剂-1基因缺陷小鼠（派-1（-/-）小鼠）相对受到保护，不会因博莱霉素给药而发生肺纤维化。我们假设其中一种保护机制可能是纤溶酶原系统增强肝细胞生长因子（HGF）作用的能力，据报道HGF在肺中具有抗纤维化作用。已知HGF通过与细胞外基质成分结合而被隔离在组织中。博来霉素给药后，我们发现派-1（-/-）小鼠支气管肺泡灌洗液中HGF蛋白水平高于野生型（派-1（+/+））小鼠。这种增加可以通过给予氨甲环酸来抑制，氨甲环酸抑制纤溶酶活性。相反，经气管内滴注尿激酶到博来霉素损伤的派-1（+/+）小鼠中以激活纤溶酶原，引起支气管肺泡灌洗液中HGF的显著增加，并引起肺中胶原积聚减少。给予抗HGF中和抗体可显著增加博来霉素损伤的PAL-1（-/-）小鼠肺中胶原蛋白的积累。这些结果支持了这样的假设，即可能通过纤溶酶依赖性机制增强HGF从细胞外基质中的释放来增加HGF的可用性，是纤溶酶原系统激活可以限制肺纤维化的重要手段。
Mice deficient in the plasminogen activator inhibitor-1 gene (PAI-1(-/-) mice) are relatively protected from developing pulmonary fibrosis from bleomycin administration. We hypothesized that one of the protective mechanisms may be the ability of the plasminogen system to enhance hepatocyte growth factor (HGF) effects, which have been reported to be anti-fibrotic in the lung. HGF is known to be sequestered in tissues by binding to extracellular matrix components. Following bleomycin administration, we found that HGF protein levels were higher in bronchoalveolar lavage fluid from PAI-1(-/-) mice compared to wild-type (PAI-1(+/+)) mice. This increase could be suppressed by administering tranexamic acid, which inhibits plasmin activity. Conversely, intratracheal instillation of urokinase into bleomycin-injured PAI-1(+/+) mice to activate plasminogen caused a significant increase in HGF within bronchoalveolar lavage and caused less collagen accumulation in the lungs. Administration of an anti-HGF neutralizing antibody markedly increased collagen accumulation in the lungs of bleomycin-injured PAL-1(-/-) mice. These results support the hypothesis that increasing the availability of HGF, possibly by enhancing its release from extracellular matrix by a plasmin-dependent mechanism, is an important means by which activation of the plasminogen system can limit pulmonary fibrosis.