title: The protective effect of recombinant human keratinocyte growth factor on radiation-induced pulmonary toxicity in rats.
abstract: OBJECTIVE
  Radiation-induced lung toxicity is a significant dose-limiting side effect of radiotherapy for thoracic tumors. Recombinant human keratinocyte growth factor (rHuKGF) has been shown to be a mitogen for type II pneumocytes. The purpose of this study was to determine whether rHuKGF prevents or ameliorates the severity of late lung damage from fractionated irradiation in a rat model.
  
  
  METHODS
  Female Fisher 344 rats were irradiated to the right hemithorax with a dose of 40 Gy/5 fractions/5 days. rHuKGF at dose of 5 mg/kg or 15 mg/kg was given via a single intravenous injection 10 min after the last fraction of irradiation. Animals were followed for 6 months after irradiation.
  
  
  RESULTS
  The breathing rate increased beginning at 6 weeks and reached a peak at 14 weeks after irradiation. The average breathing frequencies in the irradiated groups with rHuKGF (5 mg/kg and 15 mg/kg) treatment were significantly lower than that in the group receiving radiation without rHuKGF (116.5 +/- 1.0 and 115.2 +/- 0.8 vs 123.5 +/- 1.2 breaths/min, p < 0.01). The severity of lung fibrosis and the level of immunoreactivity of integrin alphavbeta6, TGFbeta1, type II TGFbeta receptor, Smad3, and phosphorylated Smad2/3 were significantly decreased only in the group receiving irradiation plus high-dose rHuKGF treatment compared with irradiation plus vehicle group, suggesting a dose response for the effect of rHuKGF.
  
  
  CONCLUSIONS
  This study is the first to demonstrate that rHuKGF treatment immediately after irradiation protects against late radiation-induced pulmonary toxicity. These results suggest that restoration of the integrity of the pulmonary epithelium via rHuKGF stimulation may downregulate the TGF-beta-mediated fibrosis pathway. These data also support the use of rHuKGF in a clinical trial designed to prevent radiation-induced lung injury.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Liguang
authors.initials: L
authors.lastname: Chen
authors.forename: David M
authors.initials: DM
authors.lastname: Brizel
authors.forename: Zahid N
authors.initials: ZN
authors.lastname: Rabbani
authors.forename: Thaddeus V
authors.initials: TV
authors.lastname: Samulski
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Farrell
authors.forename: Nicole
authors.initials: N
authors.lastname: Larrier
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Anscher
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Vujaskovic
mesh_terms: D000818:Animals; D005260:Female; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000627:therapeutic use*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000528:radiation effects; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D017564:Radiation Pneumonitis / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000627:therapeutic use; D012119:Respiration / Q000187:drug effects / Q000528:radiation effects
chemical_list: C496453:FGF7 protein, human; C496455:Fgf7 protein, rat; D011837:Radiation-Protective Agents; D011994:Recombinant Proteins; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors