Decreased pulmonary radiation resistance of manganese superoxide dismutase(MnSOD)-deficient mice is corrected by human manganese superoxide dismutase-plasmid/liposome (SOD2-PL) intratracheal gene therapy

The pulmonary ionizing radiation sensitivity of C57BL/6 Sod2(+/-) mice hete rozygous for MnSOD deficiency was compared to that Sod2(+/+) control litter mates. Embryo fibroblast cell lines from Sod2(-/-) (neonatal lethal) or Sod 2(+/-) mice produced less biochemically active MnSOD and demonstrated a sig nificantly greater in vitro radiosensitivity. No G(2)/M-phase cell cycle ar rest after 5 Gy was observed in Sod2(-/-) cells compared to the Sod2(+/-) o r Sod2(+/+) lines. Subclonal Sod2(-/-) or Sod2(+/-) embryo fibroblast lines expressing the human SOD2 transgene showed increased biochemical activity of MnSOD and radioresistance, Sod2(+/-) mice receiving 18 Gy whole-lung irr adiation died sooner and had an increased percentage of lung with organizin g alveolitis between 100 and 160 days compared to Sod2(+/+) wild-type litte rmates. Both Sod2(+/-) and Sod2(+/+) littermates injected intratracheally w ith human manganese superoxide dismutase-plasmid/liposome (SOD2-PL) complex 24 h prior to whole-lung irradiation showed decreased DNA strand breaks an d improved survival with decreased organizing alveolitis. Thus underexpress ion of MnSOD in the lungs of heterozygous Sod2(+/-) knockout mice is associ ated with increased pulmonary radiation sensitivity and parallels increased radiation sensitivity of embryo fibroblast cell lines in vitro, The restor ation of cellular radioresistance in vitro and in lungs in vivo by SOD2-PL transgene expression supports a potential role for SOD2-PL gene therapy in organ-specific radioprotection. (C) 2000 by Radiation Research Society.