University of Maryland, School of Pharmacy, Department of Pharmaceutical Sciences, Baltimore, MD.
University of Maryland, School of Medicine, Department of Radiation Oncology, Baltimore, MD 21201.
Health Phys. 2021 Oct 1;121(4):406-418. doi: 10.1097/HP.0000000000001477.
High-dose radiation exposure results in hematopoietic (H) and gastrointestinal (GI) acute radiation syndromes (ARS) followed by delayed effects of acute radiation exposure (DEARE), which include damage to lung, heart, and GI. Whereas DEARE includes inflammation and fibrosis in multiple tissues, the molecular mechanisms contributing to inflammation and to the development of fibrosis remain incompletely understood. Reports that radiation dysregulates retinoids and proteins within the retinoid pathway indicate that radiation disrupts essential nutrient homeostasis. An active metabolite of vitamin A, retinoic acid (RA), is a master regulator of cell proliferation, differentiation, and apoptosis roles in inflammatory signaling and the development of fibrosis. As facets of inflammation and fibrosis are regulated by RA, we surveyed radiation-induced changes in retinoids as well as proteins related to and targets of the retinoid pathway in the non-human primate after high dose radiation with minimal bone marrow sparing (12 Gy PBI/BM2.5). Retinoic acid was decreased in plasma as well as in lung, heart, and jejunum over time, indicating a global disruption of RA homeostasis after IR. A number of proteins associated with fibrosis and with RA were significantly altered after radiation. Together these data indicate that a local deficiency of endogenous RA presents a permissive environment for fibrotic transformation.
高剂量辐射暴露会导致造血（H）和胃肠道（GI）急性辐射综合征（ARS），随后是急性辐射暴露的延迟效应（DEARE），包括肺、心脏和胃肠道损伤。虽然 DEARE 包括多个组织的炎症和纤维化，但导致炎症和纤维化发展的分子机制仍不完全清楚。辐射会扰乱类视黄醇和类视黄醇途径中的蛋白质的报告表明，辐射会破坏必需的营养物质稳态。维生素 A 的一种活性代谢物，视黄酸（RA），是细胞增殖、分化和凋亡的主要调节剂，在炎症信号和纤维化发展中发挥作用。由于炎症和纤维化的各个方面都受到 RA 的调节，我们调查了在非人类灵长类动物中，高剂量辐射（12 Gy PBI/BM2.5，最小骨髓保留）后，视黄醇以及与视黄醇途径相关的蛋白质和靶蛋白的变化。随着时间的推移，血浆以及肺、心脏和空肠中的视黄酸减少，表明 IR 后 RA 稳态的全面破坏。与纤维化和 RA 相关的许多蛋白质在辐射后发生了显著改变。这些数据表明，局部缺乏内源性 RA 为纤维化转化提供了一个许可环境。
