The protective effect of recombinant human keratinocyte growth factor on radiation-induced pulmonary toxicity in rats.
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.
Chen
Liguang
L
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
Brizel
David M
DM
Rabbani
Zahid N
ZN
Samulski
Thaddeus V
TV
Farrell
Catherine L
CL
Larrier
Nicole
N
Anscher
Mitchell S
MS
Vujaskovic
Zeljko
Z
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
C496453:FGF7 protein, human; C496455:Fgf7 protein, rat; D011837:Radiation-Protective Agents; D011994:Recombinant Proteins; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors