Overexpression of extracellular superoxide dismutase reduces acute radiation induced lung toxicity

Zahid N. Rabbani, Mitchell S. Anscher, Rodney J. Folz, Emerald Archer, Hong Huang, Liguang Chen, Maria L. Golson, Thaddeus S. Samulski, Mark W. Dewhirst, Zeljko Vujaskovic

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

Background: Acute RT-induced damage to the lung is characterized by inflammatory changes, which proceed to the development of fibrotic lesions in the late phase of injury. Ultimately, complete structural ablation will ensue, if the source of inflammatory / fibrogenic mediators and oxidative stress is not removed or attenuated. Therefore, the purpose of this study is to determine whether overexpression of extracellular superoxide dismutase (EC-SOD) in mice ameliorates acute radiation induced injury by inhibiting activation of TGFβ1 and downregulating the Smad 3 arm of its signal transduction pathway. Methods: Whole thorax radiation (single dose, 15 Gy) was delivered to EC-SOD overexpressing transgenic (XRT-TG) and wild-type (XRT-WT) animals. Mice were sacrificed at 1 day, 1 week, 3, 6, 10 and 14 weeks. Breathing rates, right lung weights, total/differential leukocyte count, activated TGFβ1 and components of its signal transduction pathway (Smad 3 and p-Smad 2/3) were assessed to determine lung injury. Results: Irradiated wild-type (XRT-WT) animals exhibited time dependent increase in breathing rates and right lung weights, whereas these parameters were significantly less increased (p<0.05) at 3, 6, 10 and 14 weeks in irradiated transgenic (XRT-TG) mice. An inflammatory response characterized predominantly by macrophage infiltration was pronounced in XRT-WT mice. This acute inflammation was significantly attenuated (p<0.05) in XRT-TG animals at 1, 3, 6 and 14 weeks. Expression of activated TGFβ1 and components of its signal transduction pathway were significantly reduced (p<0.05) at later time-points in XRT-TG vs. XRT-WT. Conclusions: This study shows that overexpression of EC-SOD confers protection against RT-induced acute lung injury. EC-SOD appears to work, in part, via an attenuation of the macrophage response and also decreases TGFβ1 activation with a subsequent downregulation of the profibrotic TGFβ pathway.

Original languageEnglish (US)
Article number59
JournalBMC cancer
Volume5
DOIs
StatePublished - Jun 10 2005
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

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