a Department of Radiation Oncology, University of California at Los Angeles, Los Angeles, California.
b Department of Microbiology, Immunology and Molecular Genetics, University of California at Los Angeles, Los Angeles, California.
Radiat Res. 2019 Apr;191(4):323-334. doi: 10.1667/RR15231.1. Epub 2019 Feb 7.
Intensive research is underway to find new agents that can successfully mitigate the acute effects of radiation exposure. This is primarily in response to potential counterthreats of radiological terrorism and nuclear accidents but there is some hope that they might also be of value for cancer patients treated with radiation therapy. Research into mitigation countermeasures typically employs classic animal models of acute radiation syndromes (ARS) that develop after whole-body irradiation (WBI). While agents are available that successfully mitigate ARS when given after radiation exposure, their success raises questions as to whether they simply delay lethality or unmask potentially lethal radiation pathologies that may appear later in time. Life shortening is a well-known consequence of WBI in humans and experimental animals, but it is not often examined in a mitigation setting and its causes, other than cancer, are not well-defined. This is in large part because delayed effects of acute radiation exposure (DEARE) do not follow the strict time-dose phenomena associated with ARS and present as a diverse range of symptoms and pathologies with low mortality rates that can be evaluated only with the use of large cohorts of subjects, as in this study. Here, we describe chronically increased mortality rates up to 660 days in large numbers of mice given LD doses of WBI. Systemic myeloid cell activation after WBI persists in some mice and is associated with late immunophenotypic changes and hematopoietic imbalance. Histopathological changes are largely of a chronic inflammatory nature and variable incidence, as are the clinical symptoms, including late diarrhea that correlates temporally with changes in the content of the microbiome. We also describe the acute and long-term consequences of mitigating hematopoietic ARS (H-ARS) lethality after LD doses of WBI in multiple cohorts of mice treated uniformly with radiation mitigators that have a common 4-nitro-phenylsulfonamide (NPS) pharmacophore. Effective NPS mitigators dramatically decrease ARS mortality. There is slightly increased subacute mortality, but the rate of late mortalities is slowed, allowing some mice to live a normal life span, which is not the case for WBI controls. The study has broad relevance to radiation late effects and their potential mitigation and epitomizes the complex interaction between radiation-damaged tissues and immune homeostasis.
正在进行深入研究，以寻找新的药物来成功缓解辐射暴露的急性影响。这主要是为了应对放射性恐怖主义和核事故的潜在威胁，但也有一些希望这些药物对接受放射治疗的癌症患者也可能有价值。缓解对策的研究通常采用经典的急性辐射综合征（ARS）动物模型，这些模型在全身照射（WBI）后发展。虽然有一些药物在辐射暴露后使用时可以成功缓解 ARS，但它们的成功引发了一些问题，即它们是否只是延迟了致死性，还是掩盖了可能在以后出现的潜在致命辐射病理。在人类和实验动物中，全身照射导致寿命缩短是众所周知的后果，但在缓解情况下很少进行检查，除了癌症之外，其原因也没有很好地定义。这在很大程度上是因为急性辐射暴露的延迟效应（DEARE）不符合与 ARS 相关的严格时间剂量现象，并且表现为一系列不同的症状和病理，其死亡率较低，只有使用大量研究对象才能进行评估，就像本研究一样。在这里，我们描述了大量接受 LD 剂量全身照射的小鼠中高达 660 天的慢性死亡率增加。全身髓样细胞激活在一些小鼠中持续存在，并与晚期免疫表型变化和造血失衡有关。组织病理学变化主要是慢性炎症性质，发病率也不同，临床症状也包括晚期腹泻，腹泻与微生物组内容的变化时间相关。我们还描述了在多批接受均匀治疗的具有共同 4-硝基苯磺酰胺（NPS）药效团的辐射缓解剂的小鼠中，LD 剂量全身照射后缓解造血 ARS（H-ARS）致死性的急性和长期后果。有效的 NPS 缓解剂可显著降低 ARS 死亡率。亚急性死亡率略有增加，但晚期死亡率的速度减慢，使一些小鼠能够正常生存，而 WBI 对照组则不是这样。这项研究对辐射晚期效应及其潜在缓解具有广泛的意义，并体现了辐射损伤组织与免疫稳态之间的复杂相互作用。
