title: Investigations into the role of inflammation in normal tissue response to irradiation.
abstract: OBJECTIVE
  Radiation-induced inflammation and production of reactive oxygen species (ROS) play a critical role in normal tissue response. In this study we have examined some aspects of these effects in lung and skin.
  
  
  METHODS
  The superoxide dismutase (SOD) catalase mimetic, EUK-207, and genistein, an isoflavone with anti-inflammatory properties, were given post-irradiation and micronuclei (MN) formation was determined in cells derived from irradiated lung and skin. Changes in breathing rate were measured using a plethysmograph following irradiation of C57Bl6 mice knocked out for tumor necrosis factor (TNF)-alpha or its receptors, TNFR1/2, or treated with endotoxin (lipopolysaccharide - LPS).
  
  
  RESULTS
  Both EUK-207 and genistein given after irradiation caused a large reduction in MN levels observed in lung cells during 14 weeks post-irradiation but ceasing treatment resulted in a rebound in MN levels at 28 weeks post-irradiation. In contrast, treatment with EUK-207 was largely ineffective in reducing MN observed in skin cells post-irradiation. Knock-out of TNF-alpha resulted in a reduced increase in breathing rate (peak at 12 weeks post-irradiation) relative to wild-type and TNFR1/2 knock-out. Treatment with LPS 1 h post-irradiation also reduced the increase in breathing rate.
  
  
  CONCLUSIONS
  The increase in MN in lung cells after treatment with EUK-207 or genistein was stopped suggests that continuing ROS production contributes to DNA damage in lung cells over prolonged periods. That this effect was not seen in skin suggests this mechanism is less prominent in this tissue. The reduced level of radiation pneumonitis (as monitored by breathing rate changes) in animals knocked out for TNF-alpha suggests that this cytokine plays a significant role in inducing inflammation in lung following irradiation. The similar effect observed following LPS given post-irradiation suggests the possibility that such treatment modifies the long-term cyclic inflammatory response following irradiation in lungs.
authors: Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Canada. hill@uhnres.utoronto.ca
authors: Richard Peter
authors: RP
authors: Hill
authors: Asif
authors: A
authors: Zaidi
authors: Javed
authors: J
authors: Mahmood
authors: Salomeh
authors: S
authors: Jelveh
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects*; D004195:Disease Models, Animal; D005260:Female; D019833:Genistein / Q000494:pharmacology; D016014:Linear Models; D008168:Lung / Q000187:drug effects / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015162:Micronucleus Tests; D015999:Multivariate Analysis; D009942:Organometallic Compounds / Q000494:pharmacology; D017564:Radiation Pneumonitis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011855:Radiodermatitis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000528:radiation effects*; D013045:Species Specificity; D013482:Superoxide Dismutase / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism*
chemical_list: C476761:EUK 207; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D019833:Genistein; D013482:Superoxide Dismutase