title: Plasmin overcomes resistance to prostaglandin E2 in fibrotic lung fibroblasts by reorganizing protein kinase A signaling.
abstract: Collagen deposition by fibroblasts contributes to scarring in fibrotic diseases. Activation of protein kinase A (PKA) by cAMP represents a pivotal brake on fibroblast activation, and the lipid mediator prostaglandin E(2) (PGE(2)) exerts its well known anti-fibrotic actions through cAMP signaling. However, fibrotic fibroblasts from the lungs of patients with idiopathic pulmonary fibrosis, or of mice with bleomycin-induced fibrosis, are resistant to the normal collagen-inhibiting action of PGE(2). In this study, we demonstrate that plasminogen activation to plasmin restores PGE(2) sensitivity in fibrotic lung fibroblasts from human and mouse. This involves amplified PKA signaling resulting from the promotion of new interactions between AKAP9 and PKA regulatory subunit II in the perinuclear region as well as from the inhibition of protein phosphatase 2A. This is the first report to show that an extracellular mediator can dramatically reorganize and amplify the intracellular PKA-A-kinase anchoring protein signaling network and suggests a new strategy to control collagen deposition by fibrotic fibroblasts.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan 48109, USA.
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Okunishi
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Sisson
authors.forename: Steven K
authors.initials: SK
authors.lastname: Huang
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Richard H
authors.initials: RH
authors.lastname: Simon
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology; D001761:Bleomycin / Q000009:adverse effects / Q000494:pharmacology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology*; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics; D005341:Fibrinolysin / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D010120:Oxytocics / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D054758:A Kinase Anchor Proteins; C119719:AKAP9 protein, human; C464931:Akap9 protein, mouse; D000903:Antibiotics, Antineoplastic; D003598:Cytoskeletal Proteins; D008869:Microtubule-Associated Proteins; D010120:Oxytocics; D001761:Bleomycin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054648:Protein Phosphatase 2; D005341:Fibrinolysin; D015232:Dinoprostone