Small molecular inhibitor of transforming growth factor-beta protects against development of radiation-induced lung injury

Int J Radiat Oncol Biol Phys. 2008 Jul 1;71(3):829-37. doi: 10.1016/j.ijrobp.2008.02.046. Epub 2008 Apr 12.

Abstract

Purpose: To determine whether an anti-transforming growth factor-beta (TGF-beta) type 1 receptor inhibitor (SM16) can prevent radiation-induced lung injury.

Methods and materials: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azabicyclo Compounds / administration & dosage*
  • Dose-Response Relationship, Drug
  • Female
  • Radiation Injuries / etiology*
  • Radiation Injuries / prevention & control*
  • Radiation-Protective Agents / administration & dosage*
  • Radiotherapy / adverse effects*
  • Rats
  • Rats, Sprague-Dawley
  • Respiratory Distress Syndrome, Adult / etiology*
  • Respiratory Distress Syndrome, Adult / prevention & control*
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Treatment Outcome

Substances

  • Azabicyclo Compounds
  • Radiation-Protective Agents
  • SM16 compound
  • Transforming Growth Factor beta