To determine whether oral administration of an anti-transforming growth factor-ß (TGFß) receptor inhibitor can prevent radiation (RT) induced lung injury.
Materials/Methods
A single dose of 28 Gy or sham irradiation was administered to the right hemithorax of 112 Sprague-Dawley rats using 135 kV x-rays. The anti-TGFß small molecular inhibitor SM16 was mixed into the rat chow at concentrations of SM16 0.07 g/kg and SM16 0.15 g /kg and provided to the animals ad libitum. Feeding of the SM16 chow started 7 days prior to irradiation. The animals were divided into 8 groups of 14: 1) control chow (no drug) only; 2) SM 16 0.07 g/kg only (no RT); 3) SM 16 0.15 g/kg only (no RT); 4) RT + control chow; 5) RT + SM 16 0.07 g/kg; 6) RT + SM 16 0.15 g/kg; 7) RT + 3 weeks of SM 16 0.07 g/kg followed by control chow after 3 weeks; and 8) RT + 3 weeks of 0.15 g/kg SM 16 followed by control chow. From each group, 7 animals were sacrificed at 6 weeks after RT and 7 animals at 26 weeks post-RT. Each animal's body weight was recorded every week and breathing frequencies were acquired every two weeks. Histopathologic analyses were performed for inflammation/fibrosis, activation of macrophages, and expression/activation of TGF-β.
Results
Animals receiving RT + control chow had significantly lower body weights than the rats receiving RT + SM16 0.15 g/kg (p < 0.05 for weeks 3-26) and RT + 3 weeks of SM16 0.15 g/kg (p < 0.05 for weeks 1–26). The weights of animals receiving RT + SM16 0.07 g/kg and RT + 3 weeks of SM16 0.07 g/kg were not significantly different from the animals receiving RT + control chow. The average breathing frequencies in the irradiated group receiving SM16 0.15 g/kg were significantly lower than those in the group receiving RT with control chow from week 10 through week 22 (p < 0.05), while the breathing frequencies in the irradiated group receiving SM16 0.07 g/kg were significantly lower only at weeks 10, 14, and 20. At 26 weeks post-RT, the group receiving SM16 0.15 g/kg experienced a significant decrease in lung fibrosis (p = 0.016), inflammatory response (p = 0.006), and TGFß1 activity (p = 0.011). There was no significant reduction in these measures of lung injury in the group receiving SM16 0.7 g/kg, nor was there any protection for short course (3 weeks) SM16 at either dose level.
Conclusions
The ad libitum oral administration of the anti-TGFß receptor inhibitor SM16 at a dose of 0.15 g/kg reduced functional lung damage caused by the radiation while also resulting in decreased morphologic changes, inflammatory response, and activation of TGFβ at 26 weeks after RT. The data suggest a dose response for this agent, and also suggest a superiority for long term (6 month) vs. short term (3 week) dosing regimens. The use of an anti-TGFß small molecule may be useful in the prevention of radiation induced lung injury.
1Virginia Commonwealth University Medical Center, Richmond, VA
Author Disclosures: M.S. Anscher, Biogen-Idec, B. Research Grant; B. Thrasher, None; L. Zgonjanin, None; M. Corbley, Biogen-Idec, A. Employment; L. Ling, Biogen-Idec, A. Employment; Z. Vujaskovic, None.
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