Publications [#168990] of Mark W. Dewhirst

Papers Published

1. ZN Rabbani, MS Anscher, RJ Folz, E Archer, H Huang, L Chen, ML Golson, TS Samulski, MW Dewhirst, Z Vujaskovic, Overexpression of extracellular superoxide dismutase reduces acute radiation induced lung toxicity., BMC cancer, England, vol. 5 (2005), pp. 59, ISSN 1471-2407
   (last updated on 2009/12/31)

   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 TGFbeta1 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 TGFbeta1 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 TGFbeta1 and components of its signal transduction pathway were significantly reduced (p < 0.05) at later time-points in XRT-TG vs. XRT-WT. CONCLUSION: 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 TGFbeta1 activation with a subsequent downregulation of the profibrotic TGFbeta pathway.

   Keywords:
   Animals • Bronchoalveolar Lavage Fluid • Down-Regulation • Extracellular Matrix • Extracellular Space • Humans • Immunohistochemistry • Inflammation • Lung • Macrophages • Mice • Mice, Inbred C3H • Mice, Inbred C57BL • Mice, Transgenic • Oxidative Stress • Polymerase Chain Reaction • Radiation Injuries* • Respiration • Signal Transduction • Smad3 Protein • Superoxide Dismutase • Time Factors • Transforming Growth Factor beta • Transforming Growth Factor beta1 • Transgenes • biosynthesis* • enzymology* • metabolism • pathology • radiation effects*