The protective effect of recombinant human keratinocyte growth factor on radiation-induced pulmonary toxicity in rats

• Published in: International journal of radiation oncology, biology, physics Vol. 60; no. 5; p. 1520
• Main Authors: Chen, Liguang, Brizel, David M, Rabbani, Zahid N, Samulski, Thaddeus V, Farrell, Catherine L, Larrier, Nicole, Anscher, Mitchell S, Vujaskovic, Zeljko
• Format: Journal Article
• Language: English
• Published: United States 01-12-2004
• Subjects: Animals; Female; Fibroblast Growth Factor 7; Fibroblast Growth Factors - therapeutic use; Humans; Lung - drug effects; Lung - radiation effects; Radiation Injuries, Experimental - prevention & control; Radiation Pneumonitis - prevention & control; Radiation-Protective Agents - therapeutic use; Rats; Rats, Inbred F344; Recombinant Proteins - therapeutic use; Respiration - drug effects; Respiration - radiation effects
• ISSN: 0360-3016
• DOI: 10.1016/j.ijrobp.2004.07.729

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.
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.
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.
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.