title: Truncated Plasminogen Activator Inhibitor-1 Protein Protects From Pulmonary Fibrosis Mediated by Irradiation in a Murine Model.
abstract: OBJECTIVE
  To determine whether the delivery of recombinant truncated plasminogen activator inhibitor-1 (PAI-1) protein (rPAI-1(23)) would protect from the development of radiation-induced lung injury.
  
  
  METHODS
  C57Bl/6 mice received intraperitoneal injections of rPAI-1(23) (5.4 μg/kg/d) or vehicle for 18 weeks, beginning 2 days before irradiation (IR) (5 daily fractions of 6 Gy). Cohorts of mice were followed for survival (n=8 per treatment) and tissue collection (n=3 per treatment and time point). Fibrosis in lung was assessed with Masson-Trichrome staining and measurement of hydroxyproline content. Senescence was assessed with staining for β-galactosidase activity in lung and primary pneumocytes.
  
  
  RESULTS
  Hydroxyproline content in irradiated lung was significantly reduced in mice that received rPAI-1(23) compared with mice that received vehicle (IR+vehicle: 84.97 μg/lung; IR+rPAI-1(23): 56.2 μg/lung, P=.001). C57Bl/6 mice exposed to IR+vehicle had dense foci of subpleural fibrosis at 19 weeks, whereas the lungs of mice exposed to IR+rPAI-1(23) were largely devoid of fibrotic foci. Cellular senescence was significantly decreased by rPAI-1(23) treatment in primary pneumocyte cultures and in lung at multiple time points after IR.
  
  
  CONCLUSIONS
  These studies identify that rPAI-1(23) is capable of preventing radiation-induced fibrosis in murine lungs. These antifibrotic effects are associated with increased fibrin metabolism, enhanced matrix metalloproteinase-3 expression, and reduced senescence in type 2 pneumocytes. Thus, rPAI-1(23) is a novel therapeutic option for radiation-induced fibrosis.
authors.affiliation: Radiation Oncology, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Chung
authors.affiliation: Radiation Oncology, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: Grace
authors.initials: G
authors.lastname: McKay-Corkum
authors.affiliation: Radiation Oncology, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: Su
authors.initials: S
authors.lastname: Chung
authors.affiliation: Radiation Oncology, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: Ayla
authors.initials: A
authors.lastname: White
authors.affiliation: Radiation Oncology, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Scroggins
authors.affiliation: Radiation Biology Branches, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.affiliation: Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Mulligan-Kehoe
authors.affiliation: Radiation Oncology, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland. Electronic address: citrind@mail.nih.gov.
authors.forename: Deborah
authors.initials: D
authors.lastname: Citrin
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D000818:Animals; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000187:drug effects* / Q000528:radiation effects; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005337:Fibrin / Q000378:metabolism; D006909:Hydroxyproline / Q000032:analysis / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000528:radiation effects; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism / Q000627:therapeutic use*; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D017564:Radiation Pneumonitis / Q000150:complications* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; C051321:SERPINE1 protein, human; D005337:Fibrin; D003094:Collagen; D019278:Matrix Metalloproteinase 3; D006909:Hydroxyproline