title: Small molecular inhibitor of transforming growth factor-beta protects against development of radiation-induced lung injury.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298-0058, USA. manscher@mcvh-vcu.edu
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Anscher
authors.forename: Bradley
authors.initials: B
authors.lastname: Thrasher
authors.forename: Larisa
authors.initials: L
authors.lastname: Zgonjanin
authors.forename: Zahid N
authors.initials: ZN
authors.lastname: Rabbani
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Corbley
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.forename: Lihong
authors.initials: L
authors.lastname: Sun
authors.forename: Wen-Cherng
authors.initials: WC
authors.lastname: Lee
authors.forename: Leona E
authors.initials: LE
authors.lastname: Ling
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Vujaskovic
mesh_terms: 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
chemical_list: D053961:Azabicyclo Compounds; D011837:Radiation-Protective Agents; C528106:SM16 compound; D016212:Transforming Growth Factor beta