Identification of miRNA Associated with Reduced Survival after Whole-Thorax Lung Irradiation in Non-Human Primates

Thoracic exposure to ionizing radiation can lead to delayed injuries to the heart and lung that are serious and even life-threatening. These injuries are difficult to predict since they manifest over many weeks and months. To identify non-invasive, tissue-specific biomarkers for the early detection of late radiation injury, circulating microRNA (miRNA) levels were measured in non-human primates (NHP, Macaca mulatta) that received a single exposure of whole-thorax lung irradiation (WTLI) at a dose likely to result in 20% or 75% mortality within 180 days (9.8 or 10.7 Gy). Animals were observed for 270 days after WTLI. Approximately 58% of 9.8 Gy WTLI animals (7 of 12) and 94% of 10.7 Gy WTLI animals (15 out of 16) did not survive to the primary end point. Evidence of pulmonary fibrosis/pneumonitis was observed in all animals. Animals that received 10.7 Gy WTLI experienced more severe and early-onset pneumonitis, as indicated by reduced aerated lung volume, high non-sedated respiratory rate, earlier and more frequent dexamethasone treatments, and evidence of onset of heart disease. Radiation-induced changes in the circulating miRNA profile were most prominent within the first 30 days postirradiation, before the manifestation of symptoms, and included miRNA sequences known to regulate pathways associated with pulmonary fibrosis (TGF-b/SMAD signaling) and pneumonitis/inflammation (p53 signaling). The abundance of several circulating miRNA differentially expressed at day 6 or 15, such as miR-199a-3p and miR-25-3p, correlated with statistically significant differences in survival. This study supports the hypothesis that it is feasible to use plasma miRNA profiles to identify individuals at high risk of organ-specific late radiation injury. These miRNA profiles could improve radiation oncology clinical practice and serve as biomarkers to predict who might develop late complications in the aftermath of a radiological or nuclear (RAD-NUC) incident.