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

TL;DR

Molecular imaging of the lungs after radiation exposure helps predict long-term survival in rats and shows how a drug like lisinopril can reduce radiation damage.

Contribution

This study shows that early molecular lung imaging and blood markers can predict survival and treatment response after radiation.

Findings

Rats that died by day 120 had higher increases in imaging biomarkers for cell death and oxidative stress.

Lisinopril-treated rats showed reduced lung imaging biomarker responses and improved survival.

Plasma mtDAMPs levels, especially D-loop, distinguished between surviving and non-surviving rats.

Abstract

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.

Figures