title: Systemic polyethylene glycol-modified (PEGylated) superoxide dismutase and catalase mixture attenuates radiation pulmonary fibrosis in the C57/bl6 mouse.
abstract: 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.
authors.affiliation: Department of Medicine, Pulmonary, Allergy, and Critical Care Division, Thomas Jefferson University Medical Center, Philadelphia, PA 19104, USA.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Machtay
authors.forename: Arnaud
authors.initials: A
authors.lastname: Scherpereel
authors.forename: José
authors.initials: J
authors.lastname: Santiago
authors.forename: James
authors.initials: J
authors.lastname: Lee
authors.forename: Jim
authors.initials: J
authors.lastname: McDonough
authors.forename: Paul
authors.initials: P
authors.lastname: Kinniry
authors.forename: Evguenia
authors.initials: E
authors.lastname: Arguiri
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Shuvaev
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Keith
authors.initials: K
authors.lastname: Cengel
authors.forename: Charalambos C
authors.initials: CC
authors.lastname: Solomides
authors.forename: Melpo
authors.initials: M
authors.lastname: Christofidou-Solomidou
mesh_terms: 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
chemical_list: 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