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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.

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

Author information

1
Radiation Oncology, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
2
Radiation Biology Branches, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
3
Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
4
Radiation Oncology, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland. Electronic address: citrind@mail.nih.gov.

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.

PMID:
26883561
PMCID:
PMC4838903
DOI:
10.1016/j.ijrobp.2015.11.044
[Indexed for MEDLINE]
Free PMC Article

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