Short-Term Treatment with a SOD/Catalase Mimetic, EUK-207, Mitigates Pneumonitis and Fibrosis after Single-Dose Total-Body or Whole-Thoracic Irradiation

Abstract

In the event of a radiological accident or terrorist attack, whole- or partial-body exposure can injure the lungs. To simulate such an incident, we used a single fraction of total-body irradiation (TBI) or whole-thoracic irradiation to induce pneumonitis or pulmonary fibrosis, respectively, in a rat model. The superoxide dismutase and catalase mimetic EUK-207 was given by subcutaneous injection (20 mg/kg/day, 5 days per week, once daily) starting at 7 days after irradiation and stopping before pneumonitis developed. After TBI, morbidity and the increase in breathing rates associated with pneumonitis were significantly improved in rats treated with EUK-207 compared to rats receiving irradiation alone. At 42 days after TBI (the peak of pneumonitis) changes in vascular end points including pulmonary hemodynamics ex vivo and relative arterial density in lungs were also mitigated by EUK-207. At 7 months after whole-thoracic irradiation, EUK-207 reduced synthesis of collagen as assessed by the Sircol collagen assay and Masson’s trichrome staining. Our results demonstrate promise for EUK-207 as a mitigator of radiation pneumonitis and fibrosis. We also demonstrate for the first time mitigation of multiple vascular injuries in the irradiated lung in vivo by EUK-207.

Model Development and Use of ACE Inhibitors for Preclinical Mitigation of Radiation-Induced Injury to Multiple Organs

“…The dose rate for TBI was defined at the midline of the rat and was calculated to be 1.73 Gy/min using measured output of the machine and the depth dose data. The irradiation time, including appropriate timer error of the X-ray machine, was then calculated to deliver 11, 11.25 or 11.5 Gy prescription doses in one fraction as given previously ( 8 , 9 , 12 ). The total prescription dose was delivered using one posterior-to-anterior beam.…”

“…The dose at the centers of the four rat chambers varied by 2%, and rats were randomly assigned to chambers to avoid any resulting bias. All irradiated rats received a syngeneic bone marrow transplant a few hours after irradiation ( 8 , 9 , 12 ) to prevent acute hematopoietic injury. The irradiated rats were randomized for treatment with ACE inhibitors as described in each study and/or followed until all concurrent, age-matched, nondrug-treated controls were euthanized due to morbidity.…”

“…In our efforts to develop countermeasures for mitigating life-threatening radiation-induced damage to multiple organs, we have focused on the lungs and the kidneys, which are injured after total body irradiation (TBI) ( 1 – 3 ) and are some of the most sensitive organs that exhibit delayed injuries in survivors of the acute radiation hematopoietic and gastrointestinal (GI) syndromes ( 4 – 7 ). We previously developed a rat model of total body irradiation followed by a bone marrow transplant (BMT) using a 11 Gy single dose of X ray that did not cause gastrointestinal (GI) toxicity ( 8 ). Rats were followed to 100 days and damage to the lung was assessed from 42–80 days by multiple end points including histopathology.…”

“…Rats were followed to 100 days and damage to the lung was assessed from 42–80 days by multiple end points including histopathology. Survival as well as lung damage was mitigated by short-term treatment with the superoxidedismutase catalase mimetic EUK 207 ( 8 ). Moulder et al .…”

“…Radiation nephropathy progressed until rats reached the IACUC criteria for euthanization (around 140 days). Rats were seldom euthanized before 100 days after doses ≥10 Gy TBI/BMT ( 9 , 10 ), indicating that these doses did not induce lethality due to radiation pneumonitis, which occurred before 80 days ( 8 ).…”