title: Intraesophageal manganese superoxide dismutase-plasmid liposomes ameliorates novel total-body and thoracic radiation sensitivity of NOS1-/- mice.
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.
authors: Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15232, USA.
authors: Malolan S
authors: MS
authors: Rajagopalan
authors: Brandon
authors: B
authors: Stone
authors: Jean-Claude
authors: JC
authors: Rwigema
authors: Umar
authors: U
authors: Salimi
authors: Michael W
authors: MW
authors: Epperly
authors: Julie
authors: J
authors: Goff
authors: Darcy
authors: D
authors: Franicola
authors: Tracy
authors: T
authors: Dixon
authors: Shaonan
authors: S
authors: Cao
authors: Xichen
authors: X
authors: Zhang
authors: Bettina M
authors: BM
authors: Buchholz
authors: Anthony J
authors: AJ
authors: Bauer
authors: Serah
authors: S
authors: Choi
authors: Christopher
authors: C
authors: Bakkenist
authors: Hong
authors: H
authors: Wang
authors: Joel S
authors: JS
authors: Greenberger
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000528:radiation effects; D004558:Electric Stimulation; D004947:Esophagus / Q000201:enzymology*; D005772:Gastrointestinal Transit; D008081:Liposomes; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids; D013902:Radiography, Thoracic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics*
chemical_list: D008081:Liposomes; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D013482:Superoxide Dismutase