Small molecular inhibitor of transforming growth factor-beta protects against development of radiation-induced lung injury.
OBJECTIVE
To determine whether an anti-transforming growth factor-beta (TGF-beta) type 1 receptor inhibitor (SM16) can prevent radiation-induced lung injury.


METHODS
One fraction of 28 Gy or sham radiotherapy (RT) was administered to the right hemithorax of Sprague-Dawley rats. SM16 was administered in the rat chow (0.07 g/kg or 0.15 g/kg) beginning 7 days before RT. The rats were divided into eight groups: group 1, control chow; group 2, SM16, 0.07 g/kg; group 3, SM16, 0.15 g/kg; group 4, RT plus control chow; group 5, RT plus SM16, 0.07 g/kg; group 6, RT plus SM16, 0.15 g/kg; group 7, RT plus 3 weeks of SM16 0.07 g/kg followed by control chow; and group 8, RT plus 3 weeks of SM16 0.15 g/kg followed by control chow. The breathing frequencies, presence of inflammation/fibrosis, activation of macrophages, and expression/activation of TGF-beta were assessed.


RESULTS
The breathing frequencies in the RT plus SM16 0.15 g/kg were significantly lower than the RT plus control chow from Weeks 10-22 (p <0.05). The breathing frequencies in the RT plus SM16 0.07 g/kg group were significantly lower only at Weeks 10, 14, and 20. At 26 weeks after RT, the RT plus SM16 0.15 g/kg group experienced a significant decrease in lung fibrosis (p = 0.016), inflammatory response (p = 0.006), and TGF-beta1 activity (p = 0.011). No significant reduction was found in these measures of lung injury in the group that received SM16 0.7 g/kg nor for the short-course (3 weeks) SM16 at either dose level.


CONCLUSIONS
SM16 at a dose of 0.15 g/kg reduced functional lung damage, morphologic changes, inflammatory response, and activation of TGF-beta at 26 weeks after RT. The data suggest a dose response and also suggest the superiority of long-term vs. short-term dosing.
Anscher
Mitchell S
MS
Department of Radiation Oncology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298-0058, USA. manscher@mcvh-vcu.edu
Thrasher
Bradley
B
Zgonjanin
Larisa
L
Rabbani
Zahid N
ZN
Corbley
Michael J
MJ
Fu
Kai
K
Sun
Lihong
L
Lee
Wen-Cherng
WC
Ling
Leona E
LE
Vujaskovic
Zeljko
Z
D000818:Animals; D053961:Azabicyclo Compounds / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005260:Female; D011832:Radiation Injuries / Q000209:etiology* / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000008:administration & dosage*; D011878:Radiotherapy / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000209:etiology* / Q000517:prevention & control*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
D053961:Azabicyclo Compounds; D011837:Radiation-Protective Agents; C528106:SM16 compound; D016212:Transforming Growth Factor beta