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

J Clin Invest. 2010 Jun;120(6):1950-60. doi: 10.1172/JCI38369. Epub 2010 May 24.


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 E2 (PGE2). Plasminogen activation upregulated PGE2 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 PGE2 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/PGE2 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 PGE2 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 PGE2 synthesis in response to plasmin or HGF. These studies demonstrate crosstalk between plasminogen activation and PGE2 generation in the lung and provide a mechanism for the well-known antifibrotic actions of the fibrinolytic pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Bleomycin / adverse effects
  • Bleomycin / metabolism
  • Bleomycin / pharmacology
  • Collagen / adverse effects
  • Collagen / metabolism
  • Collagen / pharmacology
  • Cyclooxygenase 2 / biosynthesis*
  • Dinoprostone / biosynthesis*
  • Dinoprostone / metabolism
  • Dinoprostone / pharmacology
  • Extracellular Matrix / metabolism
  • Fibrinolysin
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Humans
  • Lung / drug effects
  • Lung / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Plasminogen / adverse effects
  • Plasminogen / metabolism*
  • Plasminogen / pharmacology
  • Plasminogen Activator Inhibitor 1 / adverse effects
  • Plasminogen Activator Inhibitor 1 / metabolism*
  • Plasminogen Activator Inhibitor 1 / pharmacology
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / metabolism*
  • Pulmonary Fibrosis / pathology
  • Receptor, PAR-1 / metabolism


  • Plasminogen Activator Inhibitor 1
  • Receptor, PAR-1
  • Bleomycin
  • Plasminogen
  • Collagen
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Fibrinolysin
  • Dinoprostone