Intraesophageal manganese superoxide dismutase-plasmid liposomes ameliorates novel total-body and thoracic radiation sensitivity of NOS1-/- mice.
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.
Rajagopalan
Malolan S
MS
Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15232, USA.
Stone
Brandon
B
Rwigema
Jean-Claude
JC
Salimi
Umar
U
Epperly
Michael W
MW
Goff
Julie
J
Franicola
Darcy
D
Dixon
Tracy
T
Cao
Shaonan
S
Zhang
Xichen
X
Buchholz
Bettina M
BM
Bauer
Anthony J
AJ
Choi
Serah
S
Bakkenist
Christopher
C
Wang
Hong
H
Greenberger
Joel S
JS
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*
D008081:Liposomes; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D013482:Superoxide Dismutase