Effects of Low-to-Moderate Doses of Gamma Radiation on Mouse Hematopoietic System

Li, Xianghong; Cui, Wanchang; Hull, Lisa; Smith, Julian C.; Kiang, Juliann G.; Xiao, Mang

doi:10.1667/rr15087.1

Cited by 25 publications

(19 citation statements)

References 35 publications

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“…Together, these findings confirmed the work of multiple other investigators (e.g. Tang et al 2017;Li et al 2018) who have demonstrated that the irradiated hematopoietic system appears to fully recover within 1-2 months, with circulating blood counts, etc., returning to pre-exposure baseline levels. Nonetheless, some groups have reported delayed defects in the HSC compartment following TBI (e.g.…”

Section: Delayed (12 Week) Effects On Hematopoiesissupporting

confidence: 89%

Acute and late effects of combined internal and external radiation exposures on the hematopoietic system

Calvi

Frisch

Kingsley

et al. 2019

International Journal of Radiation Biology

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Purpose: Incidents, such as nuclear facility accidents and the release of a 'dirty bomb', might result in not only external irradiation of personnel, but additional internal exposures through concomitant inhalation and/or ingestion of radioactive particulates. The purpose of this study was to define the impact of such a combination of radiation injuries on the hematopoietic niche. Material and methods: To assess changes in the murine hematopoietic system, we used a combined exposure of total body irradiation (TBI, 6 Gy) followed immediately by an internal (intraperitoneal) administration of 100 mCi of soluble 137 Cs. We then evaluated acute survival in combined versus single modality exposure groups, as well as assessing hematopoietic function at 12 and 26 week time points. Results: Acutely, the combination of external and internal exposures led to an unexpected delay in excretion of 137 Cs, increasing the absorbed dose in the combined exposure group and leading to mortality from an acute hematopoietic syndrome. At 12 weeks, all exposure paradigms resulted in decreased numbers of phenotypic hematopoietic stem cells (HSCs), particularly the short-term HSCs (ST-HSC); long-term HSCs (LT-HSC) were depleted only in the internal and combined exposure groups. At 26 weeks, there was significant anemia in both the TBI alone and combined exposure groups. There were decreased numbers in both the LT-and ST-HSCs and decreased functionality, as measured by competitive repopulation, was seen in all radiation groups, with the greatest effects seen in the internal and combined exposure groups. Conclusions: Our data indicate that a combined injury of sublethal external irradiation with internal contamination induces significant and persistent changes in the hematopoietic system, as may have been predicted from the literature and our own group's findings. However, a novel observation was that the combined exposure led to an alteration in the excretion kinetics of the internal contamination, increasing the acute effects beyond those anticipated. As a result, we believe that a combined exposure poses a unique challenge to the medical community during both the acute and, possibly, delayed recovery stages.

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Section: Delayed (12 Week) Effects On Hematopoiesissupporting

confidence: 89%

Acute and late effects of combined internal and external radiation exposures on the hematopoietic system

Calvi

Frisch

Kingsley

et al. 2019

International Journal of Radiation Biology

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“…All methods were developed in our group as described previously 3 . Mice were humanely euthanized for whole blood, serum and tissue collection.…”

Section: Methodsmentioning

confidence: 99%

“…These damage-associated molecular patterns (DAMPs) are endogenous molecules released from damaged cells and are important proinflammatory causal factors which can result in immune cell activation, inflammation and death 1 , 2 . In addition, a massive release of radiation-induced proinflammatory cytokines induces cell apoptosis, senescence, pyroptosis or necrosis 3 , 4 . IL-1 family members IL-1β, IL-18, and IL-33 play key roles in inflammatory and immune responses and have been described as having significant influence on the pathogenesis of diseases 5 .…”

Section: Introductionmentioning

confidence: 99%

IL-18 binding protein (IL-18BP) as a novel radiation countermeasure after radiation exposure in mice

Cui

Hull

et al. 2020

Sci Rep

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Recent studies suggested that radiation exposure causes local and systemic inflammatory responses and induces cell and tissue damage. We have reported that IL-18 plays an important role in radiation-induced injury. Here, we demonstrate that IL-18 binding protein (IL-18BP), a natural antagonist of IL-18, was significantly increased (1.7–63 fold) in mouse serum on day 1 after 0.5–10 Gy TBI. However, this high level of IL-18BP was not sufficient to neutralize the active IL-18 in irradiated mice, resulting in a radiation dose-dependent free IL-18 increase in these mice’s serum which led to pathological alterations to the irradiated cells and tissues and finally caused animal death. Administration of recombinant human (rh) IL-18BP (1.5 mg/kg) with single (24, 48 or 72 h post-TBI) or double doses (48 h and 5 days post-TBI) subcutaneous (SC) injection increased 30-day survival of CD2F1 mice after 9 Gy TBI 12.5–25% compared with the vehicle control treated group, respectively. Furthermore, the mitigative effects of rhIL-18BP included balancing the ratio of IL-18/IL-18BP and decreasing the free IL-18 levels in irradiated mouse serum and significantly increasing blood cell counts, BM hematopoietic cellularity and stem and progenitor cell clonogenicity in mouse BM. Furthermore, IL-18BP treatment inhibited the IL-18 downstream target interferon (IFN)-γ expression in mouse BM, decreased reactive oxygen species (ROS) level in the irradiated mouse heart tissues, attenuated the stress responsive factor GDF-15 (growth differentiation factor-15) and increased the intestine protector citrulline level in total body irradiated mouse serum, implicating that IL-18BP may protect multiple organs from radiation-induced inflammation and oxidative stress. Our data suggest that IL-18 plays a key role in radiation-induced cell and tissue damage and dysfunction; and for the first time demonstrated that IL-18BP counters IL-18 activation and therefore may mitigate/treat radiation-induced multiple organ injuries and increase animal survival with a wider therapeutic window from 24 h and beyond after lethal doses of radiation exposure.

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“…There is interest in using this radiation countermeasure strategy as a model for a viral-induced cytokine storm. IR has been shown to increase the expression of the following cytokines and growth factors including IL-4, IL-5, IL-10 [ 30 ], TGF- β , IL-12, IL-18 [ 31 ], type I interferons, IL-1 α , IL-1 β , IL-6, GM-CSF, and TNF- α [ 32 , 33 ]. Maximal cytokine production occurs between 4 and 24 hours following exposure to short-term radiation [ 34 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

Bradshaw

Seeds²,

Miller

et al. 2020

Oxidative Medicine and Cellular Longevity

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Human SARS-CoV-2 infection is characterized by a high mortality rate due to some patients developing a large innate immune response associated with a cytokine storm and acute respiratory distress syndrome (ARDS). This is characterized at the molecular level by decreased energy metabolism, altered redox state, oxidative damage, and cell death. Therapies that increase levels of (R)-beta-hydroxybutyrate (R-BHB), such as the ketogenic diet or consuming exogenous ketones, should restore altered energy metabolism and redox state. R-BHB activates anti-inflammatory GPR109A signaling and inhibits the NLRP3 inflammasome and histone deacetylases, while a ketogenic diet has been shown to protect mice from influenza virus infection through a protective γδ T cell response and by increasing electron transport chain gene expression to restore energy metabolism. During a virus-induced cytokine storm, metabolic flexibility is compromised due to increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that damage, downregulate, or inactivate many enzymes of central metabolism including the pyruvate dehydrogenase complex (PDC). This leads to an energy and redox crisis that decreases B and T cell proliferation and results in increased cytokine production and cell death. It is hypothesized that a moderately high-fat diet together with exogenous ketone supplementation at the first signs of respiratory distress will increase mitochondrial metabolism by bypassing the block at PDC. R-BHB-mediated restoration of nucleotide coenzyme ratios and redox state should decrease ROS and RNS to blunt the innate immune response and the associated cytokine storm, allowing the proliferation of cells responsible for adaptive immunity. Limitations of the proposed therapy include the following: it is unknown if human immune and lung cell functions are enhanced by ketosis, the risk of ketoacidosis must be assessed prior to initiating treatment, and permissive dietary fat and carbohydrate levels for exogenous ketones to boost immune function are not yet established. The third limitation could be addressed by studies with influenza-infected mice. A clinical study is warranted where COVID-19 patients consume a permissive diet combined with ketone ester to raise blood ketone levels to 1 to 2 mM with measured outcomes of symptom severity, length of infection, and case fatality rate.

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Effects of Low-to-Moderate Doses of Gamma Radiation on Mouse Hematopoietic System

Cited by 25 publications

References 35 publications

Acute and late effects of combined internal and external radiation exposures on the hematopoietic system

Acute and late effects of combined internal and external radiation exposures on the hematopoietic system

IL-18 binding protein (IL-18BP) as a novel radiation countermeasure after radiation exposure in mice

COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

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