Truncated Plasminogen Activator Inhibitor-1 Protein Protects From Pulmonary Fibrosis Mediated by Irradiation in a Murine Model

Int J Radiat Oncol Biol Phys. 2016 Apr 1;94(5):1163-72. doi: 10.1016/j.ijrobp.2015.11.044. Epub 2015 Dec 14.

Abstract

Purpose: 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 and materials: 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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Alveolar Epithelial Cells / drug effects*
  • Alveolar Epithelial Cells / metabolism
  • Alveolar Epithelial Cells / radiation effects
  • Animals
  • Cell Proliferation
  • Cellular Senescence / drug effects*
  • Cellular Senescence / radiation effects
  • Collagen / metabolism
  • Cytokines / metabolism
  • Female
  • Fibrin / metabolism
  • Hydroxyproline / analysis
  • Hydroxyproline / metabolism
  • Lung / metabolism
  • Lung / radiation effects
  • Matrix Metalloproteinase 3 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NIH 3T3 Cells
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Plasminogen Activator Inhibitor 1 / therapeutic use*
  • Pulmonary Fibrosis / etiology
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / prevention & control*
  • Radiation Pneumonitis / complications*
  • Radiation Pneumonitis / metabolism
  • Real-Time Polymerase Chain Reaction
  • Recombinant Proteins / therapeutic use*

Substances

  • Cytokines
  • Plasminogen Activator Inhibitor 1
  • Recombinant Proteins
  • SERPINE1 protein, human
  • Fibrin
  • Collagen
  • Matrix Metalloproteinase 3
  • Hydroxyproline