Systemic polyethylene glycol-modified (PEGylated) superoxide dismutase and catalase mixture attenuates radiation pulmonary fibrosis in the C57/bl6 mouse.
OBJECTIVE
Since oxidative injury is implicated in radiation-induced tissue damage to the lung, we studied systemically administered polyethylene glycol (PEGylated) antioxidant enzymes (AOEs) as pulmonary radioprotectors in mice.


METHODS
C57/bl6 Mice received 13.5 Gy single-dose irradiation to the thorax. One cohort also received 100 microg of a 1:1 mixture of PEG-AOEs {PEG-catalase and PEG-superoxide dismutase (SOD)} intravenously, pre-irradiation and subgroups were evaluated at variable time-points for inflammation and fibrosis. Potential for AOE tumor protection was studied by thoracic irradiation of mice with Lewis lung carcinoma.


RESULTS
At 48 h post-irradiation, control irradiated mice had marked elevations of tissue p21, Bax and TGF-beta1 in lungs, not seen in irradiated, PEG-AOE-treated mice. TUNEL staining of lung sections was performed at just one time-point (24 h post-irradiation) and revealed a decrease in apoptotic cells with AOE treatment. At four months post-irradiation, these mice had significantly increased pulmonary fibrosis as measured by hydroxyproline content. Mice treated with PEG-AOE prior to irradiation had 4-month hydroxyproline levels that were similar to that of unirradiated controls (p = 0.28). This corresponded to less pulmonary fibrosis as visualized histologically when compared with mice irradiated without AOEs. PEG-AOEs did not prevent post-irradiation pulmonary inflammation or lung cancer response to irradiation.


CONCLUSIONS
A mixture of PEG-SOD and PEG-CAT successfully diminished radiation pulmonary fibrosis in mice. There was also a corresponding effect on several early biomarkers of lung injury and decreased apoptosis. There were no significant effects on acute pneumonitis or tumor protection.
Machtay
Mitchell
M
Department of Medicine, Pulmonary, Allergy, and Critical Care Division, Thomas Jefferson University Medical Center, Philadelphia, PA 19104, USA.
Scherpereel
Arnaud
A
Santiago
José
J
Lee
James
J
McDonough
Jim
J
Kinniry
Paul
P
Arguiri
Evguenia
E
Shuvaev
Vladimir V
VV
Sun
Jing
J
Cengel
Keith
K
Solomides
Charalambos C
CC
Christofidou-Solomidou
Melpo
M
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002374:Catalase / Q000627:therapeutic use*; D004338:Drug Combinations; D005260:Female; D008168:Lung / Q000737:chemistry / Q000473:pathology / Q000528:radiation effects; D008175:Lung Neoplasms / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000032:analysis; D017564:Radiation Pneumonitis / Q000473:pathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D013482:Superoxide Dismutase / Q000627:therapeutic use*; D013909:Thorax / Q000528:radiation effects; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D014965:X-Rays; D051028:bcl-2-Associated X Protein / Q000235:genetics; D054462:p21-Activated Kinases
D015415:Biomarkers; D004338:Drug Combinations; D012333:RNA, Messenger; D011837:Radiation-Protective Agents; D053773:Transforming Growth Factor beta1; D051028:bcl-2-Associated X Protein; C070295:catalase-polyethylene glycol; D011092:Polyethylene Glycols; D002374:Catalase; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases