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28 June 2010 Intraesophageal Manganese Superoxide Dismutase-Plasmid Liposomes Ameliorates Novel Total-Body and Thoracic Radiation Sensitivity of NOS1−/− Mice
Malolan S. Rajagopalan, Brandon Stone, Jean-Claude Rwigema, Umar Salimi, Michael W. Epperly, Julie Goff, Darcy Franicola, Tracy Dixon, Shaonan Cao, Xichen Zhang, Bettina M. Buchholz, Anthony J. Bauer, Serah Choi, Christopher Bakkenist, Hong Wang, Joel S. Greenberger
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Abstract

The effect of deletion of the nitric oxide synthase 1 gene (NOS1−/−) on radiosensitivity was determined. In vitro, long-term cultures of bone marrow stromal cells derived from NOS1−/− were more radioresistant than cells from C57BL/6NHsd (wild-type), NOS2−/− or NOS3−/− mice. Mice from each strain received 20 Gy thoracic irradiation or 9.5 Gy total-body irradiation (TBI), and NOS1−/− mice were more sensitive to both. To determine the etiology of radiosensitivity, studies of histopathology, lower esophageal contractility, gastrointestinal transit, blood counts, electrolytes and inflammatory markers were performed; no significant differences between irradiated NOS1−/− and control mice were found. Video camera surveillance revealed the cause of death in NOS1−/− mice to be grand mal seizures; control mice died with fatigue and listlessness associated with low blood counts after TBI. NOS1−/− mice were not sensitive to brain-only irradiation. MnSOD-PL therapy delivered to the esophagus of wild-type and NOS1−/− mice resulted in equivalent biochemical levels in both; however, in NOS1−/− mice, MnSOD-PL significantly increased survival after both thoracic and total-body irradiation. The mechanism of radiosensitivity of NOS1−/− mice and its reversal by MnSOD-PL may be related to the developmental esophageal enteric neuronal innervation abnormalities described in these mice.

Malolan S. Rajagopalan, Brandon Stone, Jean-Claude Rwigema, Umar Salimi, Michael W. Epperly, Julie Goff, Darcy Franicola, Tracy Dixon, Shaonan Cao, Xichen Zhang, Bettina M. Buchholz, Anthony J. Bauer, Serah Choi, Christopher Bakkenist, Hong Wang, and Joel S. Greenberger "Intraesophageal Manganese Superoxide Dismutase-Plasmid Liposomes Ameliorates Novel Total-Body and Thoracic Radiation Sensitivity of NOS1−/− Mice," Radiation Research 174(3), 297-312, (28 June 2010). https://doi.org/10.1667/RR2019.1
Received: 1 October 2009; Accepted: 1 March 2010; Published: 28 June 2010
JOURNAL ARTICLE
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