Molecular Lung Imaging Following Exposure to Radiation Predicts Long-Term Survival in Rats

Delayed effects of acute radiation exposure (DEARE), including radiation pneumonitis (lung-DEARE), develop weeks to months after radiation exposure. Pathway-targeted biomarkers that capture early oxidative stress and cell death could improve risk stratification and provide objective measures of mitigator efficacy. The objective was to test whether molecular lung imaging predicts long-term survival and mitigator response after irradiation. Rats received 13.5 Gy leg-out partial-body irradiation with a subset treated with the radiation-injury mitigator lisinopril. Rats underwent lung imaging at weeks 2 and 4 post-irradiation with ^99mTc-duramycin (cell death) and ^99mTc-HMPAO (oxidative stress). Plasma mitochondrial damage-associated molecular patterns (mtDAMPs) were also measured. Irradiation reduced survival with animals evidencing significant pleural effusion as an indication of radiation pneumonitis, which was mitigated with lisinopril as previously shown. Lung uptake of both imaging biomarkers increased in irradiated rats between weeks 2 and 4, consistent with worsening cell death and oxidative stress. Rats that succumbed by day 120 exhibited significantly larger increases in both biomarkers than the survivors. A predictive test was developed that predicted death by day 120 with ~70% sensitivity and specificity. Plasma mtDAMPs (ND1/2 and ATPase 6/8) increased following irradiation, and the D-loop increase from week 2 to 3 separated outcomes (increase in nonsurvivors versus decrease in survivors). Both imaging and mtDAMPs data from lisinopril-treated animals showed blunted responses. Early dual-tracer molecular lung imaging predicted long-term survival after radiation exposure and tracked mitigation with lisinopril. Circulating mtDAMPs may provide complementary systemic information to further strengthen early risk stratification after radiation exposure.