title: Targeting the Renin-angiotensin system combined with an antioxidant is highly effective in mitigating radiation-induced lung damage.
abstract: OBJECTIVE
  To investigate the outcome of suppression of the renin angiotensin system using captopril combined with an antioxidant (Eukarion [EUK]-207) for mitigation of radiation-induced lung damage in rats.
  
  
  METHODS
  The thoracic cavity of female Sprague-Dawley rats was irradiated with a single dose of 11 Gy. Treatment with captopril at a dose of 40 mg/kg/d in drinking water and EUK-207 given by subcutaneous injection (8 mg/kg daily) was started 1 week after irradiation (PI) and continuing until 14 weeks PI. Breathing rate was monitored until the rats were killed at 32 weeks PI, when lung fibrosis was assessed by lung hydroxyproline content. Lung levels of the cytokine transforming growth factor-β1 and macrophage activation were analyzed by immunohistochemistry. Oxidative DNA damage was assessed by 8-hydroxy-2-deoxyguanosine levels, and lipid peroxidation was measured by a T-BARS assay.
  
  
  RESULTS
  The increase in breathing rate in the irradiated rats was significantly reduced by the drug treatments. The drug treatment also significantly decreased the hydroxyproline content, 8-hydroxy-2-deoxyguanosine and malondialdehyde levels, and levels of activated macrophages and the cytokine transforming growth factor-β1 at 32 weeks. Almost complete mitigation of these radiation effects was observed by combining captopril and EUK-207.
  
  
  CONCLUSIONS
  Captopril and EUK-207 can provide mitigation of radiation-induced lung damage out to at least 32 weeks PI after treatment given 1-14 weeks PI. Overall the combination of captopril and EUK-207 was more effective than the individual drugs used alone.
authors.affiliation: Ontario Cancer Institute and the Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Radiation Medicine Program, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Javed
authors.initials: J
authors.lastname: Mahmood
authors.affiliation: Radiation Medicine Program, STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Salomeh
authors.initials: S
authors.lastname: Jelveh
authors.affiliation: Ontario Cancer Institute and the Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Asif
authors.initials: A
authors.lastname: Zaidi
authors.affiliation: Pulmonary Center, Department of Medicine, Boston University, Boston, Massachusetts.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Doctrow
authors.affiliation: Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Meetha
authors.initials: M
authors.lastname: Medhora
authors.affiliation: Ontario Cancer Institute and the Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Departments of Medical Biophysics and Radiation Oncology, University of Toronto, Toronto, Ontario, Canada. Electronic address: hill@uhnres.utoronto.ca.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hill
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002216:Captopril / Q000008:administration & dosage / Q000494:pharmacology*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D015227:Lipid Peroxidation; D008168:Lung / Q000737:chemistry / Q000528:radiation effects*; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D011833:Radiation Injuries, Experimental / Q000188:drug therapy*; D017564:Radiation Pneumonitis / Q000188:drug therapy*; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects*; D056152:Respiratory Rate / Q000187:drug effects; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D053773:Transforming Growth Factor beta1 / Q000032:analysis
chemical_list: C476761:EUK 207; D009942:Organometallic Compounds; D011837:Radiation-Protective Agents; D017392:Thiobarbituric Acid Reactive Substances; D053773:Transforming Growth Factor beta1; D000080242:8-Hydroxy-2'-Deoxyguanosine; D002216:Captopril; D003849:Deoxyguanosine