ChromoLogic LLC, Monrovia, California 91016.
Veterinary Imaging Center of San Diego, San Diego, California 92111.
Radiat Res. 2021 Nov 1;196(5):510-522. doi: 10.1667/RADE-20-00031.1.
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 noninvasive, 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-β/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.
胸部暴露于电离辐射会导致心脏和肺部的延迟性损伤，这些损伤严重且甚至危及生命。这些损伤难以预测，因为它们会在数周和数月后显现。为了鉴定用于早期检测晚期辐射损伤的非侵入性、组织特异性生物标志物，我们测量了接受单次全胸肺照射（WTLI）的非人灵长类动物（NHP，猕猴）的循环 microRNA（miRNA）水平，照射剂量可能导致 180 天内 20%或 75%的动物死亡（9.8 或 10.7 Gy）。动物在 WTLI 后观察 270 天。大约 58%的 9.8 Gy WTLI 动物（12 只中的 7 只）和 94%的 10.7 Gy WTLI 动物（16 只中的 15 只）没有存活到主要终点。所有动物均观察到肺纤维化/肺炎的证据。接受 10.7 Gy WTLI 的动物经历了更严重和更早的肺炎，表现为充气肺容积减少、非镇静呼吸频率高、更早和更频繁地使用地塞米松治疗以及心脏病发作的证据。辐射诱导的循环 miRNA 谱变化在照射后 30 天内最为明显，早于症状出现，并包括已知调节与肺纤维化（TGF-β/SMAD 信号）和肺炎/炎症（p53 信号）相关途径的 miRNA 序列。在第 6 天或第 15 天差异表达的几种循环 miRNA（如 miR-199a-3p 和 miR-25-3p）的丰度与存活率的统计学显著差异相关。这项研究支持这样的假设，即使用血浆 miRNA 谱来识别高风险个体的器官特异性晚期辐射损伤是可行的。这些 miRNA 谱可以改进放射肿瘤学的临床实践，并作为预测放射性或核（RAD-NUC）事件后谁可能发生晚期并发症的生物标志物。
