The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice
The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice
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DOI：
10.1172/jci38369
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发表时间：
2010-06-01
影响因子：
15.9
通讯作者：
Peters-Golden, Marc
中科院分区：
文献类型：
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作者：
Bauman, Kristy A.;Wettlaufer, Scott H.;Peters-Golden, Marc
纤溶酶原激活纤溶酶可防止肺纤维化，但这种抗纤维化作用的机制仍不清楚。我们发现，缺乏纤溶酶原激活抑制剂-1 (PAI-1) 的小鼠可以免受博来霉素诱导的肺纤维化的影响，但其肺部会过度产生抗纤维化脂质介质前列腺素 E-2 (PGE(2))。纤溶酶原激活上调。 PGE(2) 在盐水和博莱霉素处理小鼠的肺泡上皮细胞、肺成纤维细胞和肺纤维细胞以及正常胎儿和成人原代人肺成纤维细胞中的合成。这种反应在 Pai1(-/-) 小鼠的细胞中被放大。尽管PGE(2) 形成的增强需要纤溶酶的产生，但它独立于蛋白酶激活受体1 (PAR-1)，而是反映了HGF 的蛋白水解激活和释放以及随后COX-2 的诱导。实验证明，HGF/COX-2/PGE(2) 轴介导 Pai1(-/-) 小鼠体内免受纤维化的保护，实验表明，HGF 受体 c-Met 的选择性抑制剂将肺胶原蛋白增加至 WT 水平，同时降低 COX-2 蛋白和 PGE(2) 水平。具有临床意义的是，来自特发性肺纤维化患者的成纤维细胞被发现诱导 COX-2 的能力存在缺陷，因此无法响应纤溶酶或 HGF 上调 PGE(2) 合成。这些研究证明了肺中纤溶酶原激活和 PGE(2) 生成之间的串扰，并为众所周知的纤溶途径抗纤维化作用提供了机制。
Plasminogen activation to plasmin protects from lung fibrosis, but the mechanism underlying this antifibrotic effect remains unclear. We found that mice lacking plasminogen activation inhibitor-1 (PAI-1), which are protected from bleomycin-induced pulmonary fibrosis, exhibit lung overproduction of the antifibrotic lipid mediator prostaglandin E-2 (PGE(2)). Plasminogen activation upregulated. PGE(2) synthesis in alveolar epithelial cells, lung fibroblasts, and lung fibrocytes from saline- and bleomycin-treated mice, as well as in normal fetal and adult primary human lung fibroblasts. This response was exaggerated in cells from Pai1(-/-) mice. Although enhanced PGE(2) formation required the generation of plasmin, it was independent of proteinase-activated receptor 1 (PAR-1) and instead reflected proteolytic activation and release of HGF with subsequent induction of COX-2. That the HGF/COX-2/PGE(2) axis mediates in vivo protection from fibrosis in Pai1(-/-) mice was demonstrated by experiments showing that a selective inhibitor of the HGF receptor c-Met increased lung collagen to WT levels while reducing COX-2 protein and PGE(2) levels. Of clinical interest, fibroblasts from patients with idiopathic pulmonary fibrosis were found to be defective in their ability to induce COX-2 and, therefore, unable to upregulate PGE(2) synthesis in response to plasmin or HGF. These studies demonstrate crosstalk between plasminogen activation and PGE(2) generation in the lung and provide a mechanism for the well-known antifibrotic actions of the fibrinolytic pathway.