Identification of miRNA signatures associated with radiation-induced late lung injury in mice

• Published in: PloS one Vol. 15; no. 5; p. e0232411
• Main Authors: Rogers, Claude J, Lukaszewicz, Agnes I, Yamada-Hanff, Jason, Micewicz, Ewa D, Ratikan, Josephine A, Starbird, Mark A, Miller, Thomas A, Nguyen, Christine, Lee, Jason T, Olafsen, Tove, Iwamoto, Keisuke S, McBride, William H, Schaue, Dörthe, Menon, Naresh
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.05.2020; Public Library of Science (PLoS)
• Subjects: Animal tissues; Animals; Biological markers; Biology and life sciences; Biomarkers; Bone morphogenetic proteins; CAT scans; Circulating MicroRNA - blood; Circulating MicroRNA - genetics; Complications; Computed tomography; Damage assessment; Diagnosis; Diagnostic imaging; Dosimetry; EDTA; Experiments; Exposure; Female; Fibrosis; Genetic aspects; Health aspects; Heart - radiation effects; Hematology; Histology; House mouse; Humans; Inflammation; Irradiation; Laboratory animals; Leukocytes; Lung - metabolism; Lung - radiation effects; Lung diseases; Lungs; Male; Medical research; Medicine and Health Sciences; Methods; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; MicroRNA; MicroRNAs; MicroRNAs - blood; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Myocardium - metabolism; Nature; NF-κB protein; Oncology; Pneumonia; Pneumonitis; Proportional Hazards Models; Radiation; Radiation (Physics); Radiation damage; Radiation effects; Radiation exposure; Radiation injuries; Radiation Injuries, Experimental - blood; Radiation Injuries, Experimental - genetics; Radiation Injuries, Experimental - metabolism; Radiation Pneumonitis - blood; Radiation Pneumonitis - genetics; Radiation Pneumonitis - metabolism; Research and Analysis Methods; Ribonucleic acid; RNA; RNA sequencing; Signaling; Smad protein; Specialty products; Species Specificity; Survival; Thorax; Tissue Distribution; Tomography; Transforming growth factors; White blood cell count; United States; Los Angeles California; California; United Kingdom > UK; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0232411

Acute radiation exposure of the thorax can lead to late serious, and even life-threatening, pulmonary and cardiac damage. Sporadic in nature, late complications tend to be difficult to predict, which prompted this investigation into identifying non-invasive, tissue-specific biomarkers for the early detection of late radiation injury. Levels of circulating microRNA (miRNA) were measured in C3H and C57Bl/6 mice after whole thorax irradiation at doses yielding approximately 70% mortality in 120 or 180 days, respectively (LD70/120 or 180). Within the first two weeks after exposure, weight gain slowed compared to sham treated mice along with a temporary drop in white blood cell counts. 52% of C3H (33 of 64) and 72% of C57Bl/6 (46 of 64) irradiated mice died due to late radiation injury. Lung and heart damage, as assessed by computed tomography (CT) and histology at 150 (C3H mice) and 180 (C57Bl/6 mice) days, correlated well with the appearance of a local, miRNA signature in the lung and heart tissue of irradiated animals, consistent with inherent differences in the C3H and C57Bl/6 strains in their propensity for developing radiation-induced pneumonitis or fibrosis, respectively. Radiation-induced changes in the circulating miRNA profile were most prominent within the first 30 days after exposure and included miRNA known to regulate inflammation and fibrosis. Importantly, early changes in plasma miRNA expression predicted survival with reasonable accuracy (88-92%). The miRNA signature that predicted survival in C3H mice, including miR-34a-5p, -100-5p, and -150-5p, were associated with pro-inflammatory NF-κB-mediated signaling pathways, whereas the signature identified in C57Bl/6 mice (miR-34b-3p, -96-5p, and -802-5p) was associated with TGF-β/SMAD signaling. This study supports the hypothesis that plasma miRNA profiles could be used to identify individuals at high risk of organ-specific late radiation damage, with applications for radiation oncology clinical practice or in the context of a radiological incident.