Overexpression of extracellular superoxide dismutase reduces acute radiation induced lung toxicity

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

doi:10.1186/1471-2407-5-59

Abstract

BackgroundAcute 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.MethodsWhole 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.ResultsIrradiated 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.ConclusionThis 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.

Highlights

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
We hypothesized that continuous over-production of reactive oxygen species (ROS), during and well after radiotherapy has been completed, is responsible for the pathogenesis of RT-induced lung injury and that continuous overexpression of extracellular superoxide dismutase (EC-SOD) would ameliorate this injury
The current evidence indicates that acute RT-induced damage to the lung is characterized by inflammatory changes, which proceed to the development of fibrotic lesions in the late phase

Summary

Introduction

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. Tissue damage and repair initiated by irradiation is associated with the production of important biological mediators, such as cytokines [4]. These cytokines perpetuate the inflammatory and fibrogenic processes associated with RT injury [5]. The relative role of cytokine dysregulation versus direct tissue injury from irradiation in the pathogenesis of acute and late toxicities is not well defined. Previous observations and recent advancements in understanding the role of these cytokines implicate transforming growth factor-β1 (TGFβ) as a key component in the development of RT-induced normal tissue injury in multiple organs, including lungs [6]

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