The Aftermath of Surviving Acute Radiation Hematopoietic Syndrome and its Mitigation

Micewicz, Ewa D.; Iwamoto, Keisuke S.; Ratikan, Josephine A.; Nguyen, Christine; Xie, Michael W.; Cheng, Genhong; Boxx, Gayle M.; Deriu, Elisa; Damoiseaux, Robert; Whitelegge, Julian P.; Ruchala, Piotr; Avetisyan, Rozeta; Jung, Michael E.; Lawson, G B; Nemeth, Elizabeta; Ganz, Tomas; Sayre, James W.; McBride, William H.; Schaue, Dörthe

doi:10.1667/rr15231.1

Cited by 17 publications

(18 citation statements)

References 69 publications

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“…Nrf2 also regulates PU.1, the master myeloid cell regulator [65], probably through NAD(P)H:quinone oxidoreductase, whose loss leads to myeloid hyperplasia [66]. However, a common result is a long-term defect in HSC reconstituting ability and continuing cycles of oxidative and reductive stress [61,67] and inflammation, with a myeloid shift; a pattern that is repeatedly reinforced [68,69]. These chronic inflammatory events are a hallmark of late radiation effects, including life shortening [69].…”

Section: Radiation Tissue Damage 649mentioning

confidence: 99%

“…However, a common result is a long-term defect in HSC reconstituting ability and continuing cycles of oxidative and reductive stress [61,67] and inflammation, with a myeloid shift; a pattern that is repeatedly reinforced [68,69]. These chronic inflammatory events are a hallmark of late radiation effects, including life shortening [69]. G-CSF [70] and probably other inflammatory stimuli can exacerbate the HSC defect, which raises questions as to the use of CSFs as mitigators of radiation damage.…”

Section: Radiation Tissue Damage 649mentioning

confidence: 99%

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Radiation‐induced tissue damage and response

McBride

Schaue

2020

The Journal of Pathology

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Normal tissue responses to ionizing radiation have been a major subject for study since the discovery of X-rays at the end of the 19th century. Shortly thereafter, time-dose relationships were established for some normal tissue endpoints that led to investigations into how the size of dose per fraction and the quality of radiation affected outcome. The assessment of the radiosensitivity of bone marrow stem cells using colony-forming assays by Till and McCulloch prompted the establishment of in situ clonogenic assays for other tissues that added to the radiobiology toolbox. These clonogenic and functional endpoints enabled mathematical modeling to be performed that elucidated how tissue structure, and in particular turnover time, impacted clinically relevant fractionated radiation schedules. More recently, lineage tracing technology, advanced imaging and single cell sequencing have shed further light on the behavior of cells within stem, and other, cellular compartments, both in homeostasis and after radiation damage. The discovery of heterogeneity within the stem cell compartment and plasticity in response to injury have added new dimensions to the consideration of radiation-induced tissue damage. Clinically, radiobiology of the 20th century garnered wisdom relevant to photon treatments delivered to a fairly wide field at around 2 Gy per fraction, 5 days per week, for 5-7 weeks. Recently, the scope of radiobiology has been extended by advances in technology, imaging and computing, as well as by the use of charged particles. These allow radiation to be delivered more precisely to tumors while minimizing the amount of normal tissue receiving high doses. One result has been an increase in the use of schedules with higher doses per fraction given in a shorter time frame (hypofractionation). We are unable to cover these new technologies in detail in this review, just as we must omit low-dose stochastic effects, and many aspects of dose, dose rate and radiation quality. We argue that structural diversity and plasticity within tissue compartments provides a general context for discussion of most radiation responses, while acknowledging many omissions.

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Section: Radiation Tissue Damage 649mentioning

confidence: 99%

Section: Radiation Tissue Damage 649mentioning

confidence: 99%

Radiation‐induced tissue damage and response

McBride

Schaue

2020

The Journal of Pathology

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“…Rodent models are applied for identifying potential MCMs and to study their in-vivo mechanisms of action. The literature includes several studies conducted over a decade, which defines the H-ARS small models against Total Body Irradiation (TBI) 9,15,18,20,34 . Similar TBI induced H-ARS studies are also reported in large animals such as mini pig and NHPs [35][36][37][38] .…”

Section: Discussionmentioning

confidence: 99%

Development of hematopoietic syndrome mice model for localized radiation exposure

Yashavarddhan

Sharma

Chaudhary

et al. 2021

Sci Rep

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Current models to study the hematopoietic syndrome largely rely on the uniform whole-body exposures. However, in the radio-nuclear accidents or terrorist events, exposure can be non-uniform. The data available on the non-uniform exposures is limited. Thus, we have developed a mice model for studying the hematopoietic syndrome in the non-uniform or partial body exposure scenarios using the localized cobalt60 gamma radiation exposure. Femur region of Strain ‘A’ male mice was exposed to doses ranging from 7 to 20 Gy. The 30 day survival assay showed 19 Gy as LD100 and 17 Gy as LD50. We measured an array of cytokines and important stem cell markers such as IFN-γ, IL-3, IL-6, GM-CSF, TNF-α, G-CSF, IL-1α, IL-1β, CD 34 and Sca 1. We found significant changes in IL-6, GM-CSF, TNF-α, G-CSF, and IL-1β levels compared to untreated groups and amplified levels of CD 34 and Sca 1 positive population in the irradiated mice compared to the untreated controls. Overall, we have developed a mouse model of the hematopoietic acute radiation syndrome that might be useful for understanding of the non-uniform body exposure scenarios. This may also be helpful in the screening of drugs intended for individuals suffering from radiation induced hematopoietic syndrome.

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“…Several animal models, primarily non-human primates and rodents, have been developed to study the delayed effects of acute radiation exposure [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ]. These models mostly address the late effects in survivors following exposure to high doses of radiation.…”

Section: Discussionmentioning

confidence: 99%

Late Health Effects of Partial Body Irradiation Injury in a Minipig Model Are Associated with Changes in Systemic and Cardiac IGF-1 Signaling

Hritzo¹,

Aghdam²,

Legesse³

et al. 2021

IJMS

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Clinical, epidemiological, and experimental evidence demonstrate non-cancer, cardiovascular, and endocrine effects of ionizing radiation exposure including growth hormone deficiency, obesity, metabolic syndrome, diabetes, and hyperinsulinemia. Insulin-like growth factor-1 (IGF-1) signaling perturbations are implicated in development of cardiovascular disease and metabolic syndrome. The minipig is an emerging model for studying radiation effects given its high analogy to human anatomy and physiology. Here we use a minipig model to study late health effects of radiation by exposing male Göttingen minipigs to 1.9–2.0 Gy X-rays (lower limb tibias spared). Animals were monitored for 120 days following irradiation and blood counts, body weight, heart rate, clinical chemistry parameters, and circulating biomarkers were assessed longitudinally. Collagen deposition, histolopathology, IGF-1 signaling, and mRNA sequencing were evaluated in tissues. Our findings indicate a single exposure induced histopathological changes, attenuated circulating IGF-1, and disrupted cardiac IGF-1 signaling. Electrolytes, lipid profiles, liver and kidney markers, and heart rate and rhythm were also affected. In the heart, collagen deposition was significantly increased and transforming growth factor beta-1 (TGF-beta-1) was induced following irradiation; collagen deposition and fibrosis were also observed in the kidney of irradiated animals. Our findings show Göttingen minipigs are a suitable large animal model to study long-term effects of radiation exposure and radiation-induced inhibition of IGF-1 signaling may play a role in development of late organ injuries.

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The Aftermath of Surviving Acute Radiation Hematopoietic Syndrome and its Mitigation

Cited by 17 publications

References 69 publications

Radiation‐induced tissue damage and response

Radiation‐induced tissue damage and response

Development of hematopoietic syndrome mice model for localized radiation exposure

Late Health Effects of Partial Body Irradiation Injury in a Minipig Model Are Associated with Changes in Systemic and Cardiac IGF-1 Signaling

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