Pneumonitis and
fibrosis are potentially lethal, delayed effects of acute radiation exposure. In this study, male rhesus macaques received whole-thorax lung irradiation (WTLI) with a target dose of 10.74 Gy prescribed to midplane at a dose rate of 0.80 ± 0.05 Gy/min using 6 MV
linear accelerator-derived photons. The study design was comprised of four animal cohorts: one control and three treated with
AEOL 10150 (n = 20 animals per cohort).
AEOL 10150, a
metalloporphyrin antioxidant,
superoxide dismutase mimetic was administered by daily
subcutaneous injection at 5 mg/kg in each of three schedules, beginning 24 ± 2 h postirradiation: from day 1 to day 28, day 1 to day 60 or a divided regimen from day 1 to day 28 plus day 60 to day 88. Control animals received
0.9% saline injections from day 1 to day 28. All animals received medical management and were followed for 180 days. Computed tomography (CT) scan and baseline hematology values were assessed prior to WTLI. Postirradiation monthly CT scans were collected, and images were analyzed for evidence of
lung injury (
pneumonitis,
fibrosis, pleural and
pericardial effusion) based on differences in radiodensity characteristics of the normal versus damaged lung. The primary end point was survival to 180 days based on all-cause mortality. The latency, incidence and severity of
lung injury were assessed through clinical, radiographic and histological parameters. A clear survival relationship was observed with the
AEOL 10150 treatment schedule and time after lethal WTLI. The day 1-60 administration schedule increased survival from 25 to 50%, mean survival time of decedents and the latency to nonsedated respiratory rate to >60 or >80 breaths/min and diminished quantitative radiographic
lung injury as determined by CT scans. It did not affect incidence or severity of
pneumonitis/
fibrosis as determined by histological evaluation,
pleural effusion or
pericardial effusion as determined by CT scans. Analysis of the Kaplan-Meier survival curves suggested that treatment efficacy could be increased by extending the treatment schedule to 90 days or longer after WTLI. No survival improvement was noted in the
AEOL 10150 cohorts treated from day 1-28 or using the divided schedule of day 1-28 plus day 60-88. These results suggest that
AEOL 10150 may be an effective medical countermeasure against severe and lethal radiation-induced
lung injury.