title: The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Kristy A
authors.initials: KA
authors.lastname: Bauman
authors.forename: Scott H
authors.initials: SH
authors.lastname: Wettlaufer
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Okunishi
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Vannella
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Stoolman
authors.forename: Steven K
authors.initials: SK
authors.lastname: Huang
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Courey
authors.forename: Eric S
authors.initials: ES
authors.lastname: White
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Richard H
authors.initials: RH
authors.lastname: Simon
authors.forename: Galen B
authors.initials: GB
authors.lastname: Toews
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Sisson
authors.forename: Bethany B
authors.initials: BB
authors.lastname: Moore
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
mesh_terms: D000328:Adult; D000818:Animals; D001761:Bleomycin / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D003094:Collagen / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D015232:Dinoprostone / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D005341:Fibrinolysin; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010958:Plasminogen / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D044463:Receptor, PAR-1 / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D044463:Receptor, PAR-1; D001761:Bleomycin; D010958:Plasminogen; D003094:Collagen; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D005341:Fibrinolysin; D015232:Dinoprostone