The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice

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.