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

Journal Article · Fri Apr 01 04:00:00 EDT 2016 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/J.IJROBP.2015.11.044· OSTI ID:22645159

Chung, Eun Joo; McKay-Corkum, Grace; Chung, Su; White, Ayla; Scroggins, Bradley T. ^[1]; Mitchell, James B. ^[2]; Mulligan-Kehoe, Mary Jo ^[3]; Citrin, Deborah ^[1]

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1. Radiation Oncology, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland (United States)
2. Radiation Biology Branches, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland (United States)
3. Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire (United States)

Purpose: To determine whether the delivery of recombinant truncated plasminogen activator inhibitor-1 (PAI-1) protein (rPAI-1{sub 23}) would protect from the development of radiation-induced lung injury. Methods and Materials: C57Bl/6 mice received intraperitoneal injections of rPAI-1{sub 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{sub 23} compared with mice that received vehicle (IR+vehicle: 84.97 μg/lung; IR+rPAI-1{sub 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{sub 23} were largely devoid of fibrotic foci. Cellular senescence was significantly decreased by rPAI-1{sub 23} treatment in primary pneumocyte cultures and in lung at multiple time points after IR. Conclusions: These studies identify that rPAI-1{sub 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{sub 23} is a novel therapeutic option for radiation-induced fibrosis.

• OSTI ID: 22645159
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Journal Name: International Journal of Radiation Oncology, Biology and Physics Journal Issue: 5 Vol. 94; ISSN IOBPD3; ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
FIBROSIS
GY RANGE 01-10
INTRAPERITONEAL INJECTION
IRRADIATION
LUNGS
MICE
PLASMINOGEN
RADIOTHERAPY