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Item Age and Sex Divergence in Hematopoietic Radiosensitivity in Aged Mouse Models of the Hematopoietic Acute Radiation Syndrome(BioOne, 2022) Patterson, Andrea M.; Vemula, Sasidhar; Plett, P. Artur; Sampson, Carol H.; Chua, Hui Lin; Fisher, Alexa; Wu, Tong; Sellamuthu, Rajendran; Feng, Hailin; Katz, Barry P.; DesRosiers, Colleen M.; Pelus, Louis M.; Cox, George N.; MacVittie, Thomas J.; Orschell, Christie M.; Medicine, School of MedicineThe hematopoietic system is highly sensitive to stress from both aging and radiation exposure, and the hematopoietic acute radiation syndrome (H-ARS) should be modeled in the geriatric context separately from young for development of age-appropriate medical countermeasures (MCMs). Here we developed aging murine H-ARS models, defining radiation dose response relationships (DRRs) in 12-month-old middle-aged and 24-month-old geriatric male and female C57BL/6J mice, and characterized diverse factors affecting geriatric MCM testing. Groups of approximately 20 mice were exposed to ∼10 different doses of radiation to establish radiation DRRs for estimation of the LD50/30. Radioresistance increased with age and diverged dramatically between sexes. The LD50/30 in young adult mice averaged 853 cGy and was similar between sexes, but increased in middle age to 1,005 cGy in males and 920 cGy in females, with further sex divergence in geriatric mice to 1,008 cGy in males but 842 cGy in females. Correspondingly, neutrophils, platelets, and functional hematopoietic progenitor cells were all increased with age and rebounded faster after irradiation. These effects were higher in aged males, and neutrophil dysfunction was observed in aged females. Upstream of blood production, hematopoietic stem cell (HSC) markers associated with age and myeloid bias (CD61 and CD150) were higher in geriatric males vs. females, and sex-divergent gene signatures were found in HSCs relating to cholesterol metabolism, interferon signaling, and GIMAP family members. Fluid intake per gram body weight decreased with age in males, and decreased after irradiation in all mice. Geriatric mice of substrain C57BL/6JN sourced from the National Institute on Aging were significantly more radiosensitive than C57BL/6J mice from Jackson Labs aged at our institution, indicating mouse source and substrain should be considered in geriatric radiation studies. This work highlights the importance of sex, vendor, and other considerations in studies relating to hematopoiesis and aging, identifies novel sex-specific functional and molecular changes in aging hematopoietic cells at steady state and after irradiation, and presents well-characterized aging mouse models poised for MCM efficacy testing for treatment of acute radiation effects in the elderly.Item Aging negatively impacts the ability of megakaryocytes to stimulate osteoblast proliferation and bone mass(Elsevier, 2019) Maupin, Kevin A.; Himes, Evan R.; Plett, Artur P.; Chua, Hui Lin; Singh, Pratibha; Ghosh, Joydeep; Mohamad, Safa F.; Abeysekera, Irushi; Fisher, Alexa; Sampson, Carol; Hong, Jung-Min; Childress, Paul; Alvarez, Marta; Srour, Edward F.; Bruzzaniti, Angela; Pelus, Louis M.; Orschell, Christie M.; Kacena, Melissa A.; Orthopaedic Surgery, School of MedicineOsteoblast number and activity decreases with aging, contributing to the age-associated decline of bone mass, but the mechanisms underlying changes in osteoblast activity are not well understood. Here, we show that the age-associated bone loss critically depends on impairment of the ability of megakaryocytes (MKs) to support osteoblast proliferation. Co-culture of osteoblast precursors with young MKs is known to increase osteoblast proliferation and bone formation. However, co-culture of osteoblast precursors with aged MKs resulted in significantly fewer osteoblasts compared to co-culture with young MKs, and this was associated with the downregulation of transforming growth factor beta. In addition, the ability of MKs to increase bone mass was attenuated during aging as transplantation of GATA1low/low hematopoietic donor cells (which have elevated MKs/MK precursors) from young mice resulted in an increase in bone mass of recipient mice compared to transplantation of young wild-type donor cells, whereas transplantation of GATA1low/low donor cells from old mice failed to enhance bone mass in recipient mice compared to transplantation of old wild-type donor cells. These findings suggest that the preservation or restoration of the MK-mediated induction of osteoblast proliferation during aging may hold the potential to prevent age-associated bone loss and resulting fractures.Item Cardiac and Renal Delayed Effects of Acute Radiation Exposure: Organ Differences in Vasculopathy, Inflammation, Senescence and Oxidative Balance(Radiation Research Society, 2019-05) Unthank, Joseph L.; Ortiz, Miguel; Trivedi, Hina; Pelus, Louis M.; Sampson, Carol H.; Sellamuthu, Rajendran; Fisher, Alexa; Chua, Hui Lin; Plett, Artur; Orschel, Christie M.; Cohen, Eric P.; Miller, Steven J.; Surgery, School of MedicineWe have previously shown significant pathology in the heart and kidney of murine hematopoietic-acute radiation syndrome (H-ARS) survivors of 8.7-9.0 Gy total-body irradiation (TBI). The goal of this study was to determine temporal relationships in the development of vasculopathy and the progression of renal and cardiovascular delayed effects of acute radiation exposure (DEARE) at TBI doses less than 9 Gy and to elucidate the potential roles of senescence, inflammation and oxidative stress. Our results show significant loss of endothelial cells in coronary arteries by 4 months post-TBI (8.53 or 8.72 Gy of gamma radiation). This loss precedes renal dysfunction and interstitial fibrosis and progresses to abnormalities in the arterial media and adventitia and loss of coronary arterioles. Major differences in radiation-induced pathobiology exist between the heart and kidney in terms of vasculopathy progression and also in indices of inflammation, senescence and oxidative imbalance. The results of this work suggest a need for different medical countermeasures for multiple targets in different organs and at various times after acute radiation injury to prevent the progression of DEARE.Item Delayed Effects of Acute Radiation Exposure in a Murine Model of the H-ARS: Multiple-Organ Injury Consequent to <10 Gy Total Body Irradiation(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2015-11) Unthank, Joseph L.; Miller, Steven J.; Quickery, Ariel K.; Ferguson, Ethan L.; Wang, Meijing; Sampson, Carol H.; Chua, Hui Lin; DiStasi, Matthew R.; Feng, Hailin; Fisher, Alexa; Katz, Barry P.; Plett, P. Artur; Sandusky, George E.; Sellamuthu, Rajendran; Vemula, Sasidhar; Cohen, Eric P.; MacVittie, Thomas J.; Orschell, Christie M.; Department of Surgery, School of MedicineThe threat of radiation exposure from warfare or radiation accidents raises the need for appropriate animal models to study the acute and chronic effects of high dose rate radiation exposure. The goal of this study was to assess the late development of fibrosis in multiple organs (kidney, heart, and lung) in survivors of the C57BL/6 mouse model of the hematopoietic-acute radiation syndrome (H-ARS). Separate groups of mice for histological and functional studies were exposed to a single uniform total body dose between 8.53 and 8.72 Gy of gamma radiation from a Cs radiation source and studied 1-21 mo later. Blood urea nitrogen levels were elevated significantly in the irradiated mice at 9 and 21 mo (from ∼22 to 34 ± 3.8 and 69 ± 6.0 mg dL, p < 0.01 vs. non-irradiated controls) and correlated with glomerosclerosis (29 ± 1.8% vs. 64 ± 9.7% of total glomeruli, p < 0.01 vs. non-irradiated controls). Glomerular tubularization and hypertrophy and tubular atrophy were also observed at 21 mo post-total body irradiation (TBI). An increase in interstitial, perivascular, pericardial and peribronchial fibrosis/collagen deposition was observed from ∼9-21 mo post-TBI in kidney, heart, and lung of irradiated mice relative to age-matched controls. Echocardiography suggested decreased ventricular volumes with a compensatory increase in the left ventricular ejection fraction. The results indicate that significant delayed effects of acute radiation exposure occur in kidney, heart, and lung in survivors of the murine H-ARS TBI model, which mirrors pathology detected in larger species and humans at higher radiation doses focused on specific organs.Item Development of a Model of the Acute and Delayed Effects of High Dose Radiation Exposure in Jackson Diversity Outbred Mice; Comparison to Inbred C57BL/6 Mice(Wolters Kluwer, 2020-11) Patterson, Andrea M.; Plett, P. Artur; Chua, Hui Lin; Sampson, Carol H.; Fisher, Alexa; Feng, Hailin; Unthank, Joseph L.; Miller, Steve J.; Katz, Barry P.; MacVittie, Thomas J.; Orschell, Christie M.; Medicine, School of MedicineDevelopment of medical countermeasures against radiation relies on robust animal models for efficacy testing. Mouse models have advantages over larger species due to economics, ease of conducting aging studies, existence of historical databases, and research tools allowing for sophisticated mechanistic studies. However, the radiation dose-response relationship of inbred strains is inherently steep and sensitive to experimental variables, and inbred models have been criticized for lacking genetic diversity. Jackson Diversity Outbred (JDO) mice are the most genetically diverse strain available, developed by the Collaborative Cross Consortium using eight founder strains, and may represent a more accurate model of humans than inbred strains. Herein, models of the Hematopoietic-Acute Radiation Syndrome and the Delayed Effects of Acute Radiation Exposure were developed in JDO mice and compared to inbred C57BL/6. The dose response relationship curve in JDO mice mirrored the more shallow curves of primates and humans, characteristic of genetic diversity. JDO mice were more radioresistant than C57BL/6 and differed in sensitivity to antibiotic countermeasures. The model was validated with pegylated-G-CSF, which provided significantly enhanced 30-d survival and accelerated blood recovery. Long-term JDO survivors exhibited increased recovery of blood cells and functional bone marrow hematopoietic progenitors compared to C57BL/6. While JDO hematopoietic stem cells declined more in number, they maintained a greater degree of quiescence compared to C57BL/6, which is essential for maintaining function. These JDO radiation models offer many of the advantages of small animals with the genetic diversity of large animals, providing an attractive alternative to currently available radiation animal models.Item Further Characterization of Multi-Organ DEARE and Protection by 16,16 Dimethyl Prostaglandin E2 in a Mouse Model of the Hematopoietic Acute Radiation Syndrome(BioOne, 2023) Wu, Tong; Pelus, Louis M.; Plett, P. Artur; Sampson, Carol H.; Chua, Hui Lin; Fisher, Alexa; Feng, Hailin; Liu, Liqiong; Li, Hongge; Ortiz, Miguel; Chittajallu, Supriya; Luo, Qianyi; Bhatwadekar, Ashay D.; Meyer, Timothy B.; Zhang, Xin; Zhou, Daohong; Fischer, Kathryn D.; McKinzie, David L.; Miller, Steven J.; Orschell, Christie M.; Medicine, School of MedicineSurvivors of acute radiation exposure suffer from the delayed effects of acute radiation exposure (DEARE), a chronic condition affecting multiple organs, including lung, kidney, heart, gastrointestinal tract, eyes, and brain, and often causing cancer. While effective medical countermeasures (MCM) for the hematopoietic-acute radiation syndrome (H-ARS) have been identified and approved by the FDA, development of MCM for DEARE has not yet been successful. We previously documented residual bone marrow damage (RBMD) and progressive renal and cardiovascular DEARE in murine survivors of H-ARS, and significant survival efficacy of 16,16-dimethyl prostaglandin E2 (dmPGE2) given as a radioprotectant or radiomitigator for H-ARS. We now describe additional DEARE (physiological and neural function, progressive fur graying, ocular inflammation, and malignancy) developing after sub-threshold doses in our H-ARS model, and detailed analysis of the effects of dmPGE2 administered before (PGE-pre) or after (PGE-post) lethal total-body irradiation (TBI) on these DEARE. Administration of PGE-pre normalized the twofold reduction of white blood cells (WBC) and lymphocytes seen in vehicle-treated survivors (Veh), and increased the number of bone marrow (BM) cells, splenocytes, thymocytes, and phenotypically defined hematopoietic progenitor cells (HPC) and hematopoietic stem cells (HSC) to levels equivalent to those in non-irradiated age-matched controls. PGE-pre significantly protected HPC colony formation ex vivo by >twofold, long term-HSC in vivo engraftment potential up to ninefold, and significantly blunted TBI-induced myeloid skewing. Secondary transplantation documented continued production of LT-HSC with normal lineage differentiation. PGE-pre reduced development of DEARE cardiovascular pathologies and renal damage; prevented coronary artery rarefication, blunted progressive loss of coronary artery endothelia, reduced inflammation and coronary early senescence, and blunted radiation-induced increase in blood urea nitrogen (BUN). Ocular monocytes were significantly lower in PGE-pre mice, as was TBI-induced fur graying. Increased body weight and decreased frailty in male mice, and reduced incidence of thymic lymphoma were documented in PGE-pre mice. In assays measuring behavioral and cognitive functions, PGE-pre reduced anxiety in females, significantly blunted shock flinch response, and increased exploratory behavior in males. No effect of TBI was observed on memory in any group. PGE-post, despite significantly increasing 30-day survival in H-ARS and WBC and hematopoietic recovery, was not effective in reducing TBI-induced RBMD or any other DEARE. In summary, dmPGE2 administered as an H-ARS MCM before lethal TBI significantly increased 30-day survival and ameliorated RBMD and multi-organ and cognitive/behavioral DEARE to at least 12 months after TBI, whereas given after TBI, dmPGE2 enhances survival from H-ARS but has little impact on RBMD or other DEARE.Item The H-ARS Dose Response Relationship (DRR): Validation and Variables(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2015-11) Plett, P. Artur; Sampson, Carol H.; Chua, Hui Lin; Jackson, William; Vemula, Sasidhar; Sellamuthu, Rajendran; Fisher, Alexa; Feng, Hailin; Wu, Tong; MacVittie, Thomas J.; Orschell, Christie M.; Department of Medicine, School of MedicineManipulations of lethally-irradiated animals, such as for administration of pharmaceuticals, blood sampling, or other laboratory procedures, have the potential to induce stress effects that may negatively affect morbidity and mortality. To investigate this in a murine model of the hematopoietic acute radiation syndrome, 20 individual survival efficacy studies were grouped based on the severity of the administration (Admn) schedules of their medical countermeasure (MCM) into Admn 1 (no injections), Admn 2 (1-3 injections), or Admn 3 (29 injections or 6-9 oral gavages). Radiation doses ranged from LD30/30 to LD95/30. Thirty-day survival of vehicle controls in each group was used to construct radiation dose lethality response relationship (DRR) probit plots, which were compared statistically to the original DRR from which all LDXX/30 for the studies were obtained. The slope of the Admn 3 probit was found to be significantly steeper (5.190) than that of the original DRR (2.842) or Admn 2 (2.009), which were not significantly different. The LD50/30 for Admn 3 (8.43 Gy) was less than that of the original DRR (8.53 Gy, p < 0.050), whereas the LD50/30 of other groups were similar. Kaplan-Meier survival curves showed significantly worse survival of Admn 3 mice compared to the three other groups (p = 0.007). Taken together, these results show that stressful administration schedules of MCM can negatively impact survival and that dosing regimens should be considered when constructing DRR to use in survival studies.Item Immune Reconstitution and Thymic Involution in the Acute and Delayed Hematopoietic Radiation Syndromes(Wolters Kluwer, 2020) Wu, Tong; Plett, P. Artur; Chua, Hui Lin; Jacobsen, Max; Sandusky, George E.; MacVittie, Thomas J.; Orschell, Christie M.; Medicine, School of MedicineLymphoid lineage recovery and involution after exposure to potentially lethal doses of ionizing radiation have not been well defined, especially the long-term effects in aged survivors and with regard to male / female differences. To examine these questions, male and female C57BL/6 mice were exposed to lethal radiation at 12 weeks of age in a model of the Hematopoietic-Acute Radiation Syndrome, and bone marrow, thymus, spleen and peripheral blood examined up to 24 months of age for the lymphopoietic Delayed Effects of Acute Radiation Exposure. Aged mice showed myeloid skewing and incomplete lymphocyte recovery in all lymphoid tissues. Spleen and peripheral blood both exhibited a mono-phasic recovery pattern while thymus demonstrated a bi-phasic pattern. Naïve T cells in blood and spleen and all subsets of thymocytes were decreased in aged irradiated mice compared to age-matched non-irradiated controls. Of interest, irradiated males experienced significantly improved reconstitution of thymocyte subsets and peripheral blood elements compared to females. Bone marrow from aged irradiated survivors was significantly deficient in the primitive lymphoid-primed multipotent progenitors and common lymphoid progenitors, which were only 8–10% of levels in aged-matched non-irradiated controls. Taken together, these analyses define significant age- and sex-related deficiencies at all levels of lymphopoiesis throughout the lifespan of survivors of the Hematopoietic-Acute Radiation Syndrome, and may provide a murine model suitable for assessing the efficacy of potential medical countermeasures and therapeutic strategies to alleviate the severe immune suppression that occurs after radiation exposure.Item Increased Incidence of Lymphosarcoma in Long-Term Murine Survivors of Lethal Radiation: A Classification of Subtypes(Office of the Vice Chancellor for Research, 2013-04-05) Spencer, Cleandrea; Chua, Hui Lin; Plett, Arthur; Sampson, Carol; Joshi, Mandar; Roberts, Christopher S.; Lipking, Kelsey; Orschell, Christie M.; Sandusky, George E.Residual bone marrow damage (RBMD) persists for years following exposure to radiation and is thought to be due to decreased self-renewal of hematopoietic stem cells (HSC). We previously examined RBMD in murine survivors of lethal radiation modeling a terrorist event [800cGy total-body irradiation (TBI)]. We reported severely deficient HSC potential up to 20mo post-TBI compared to non-TBI age-matched controls, evidenced by minimal engraftment skewed to myeloid cells. CBC and BM cellularity were decreased in TBI mice, most dramatically in old age (>16mo). The percentage of some hematopoietic progenitors was consistently increased in TBI mice (~1.4x higher than non-TBI) possibly due to an increased cell cycling rate compared to non-TBI cells. Of interest, we now report the occurrence of a thymic mass developing in 13-24% of TBI mice 2-19 months post-TBI, compared to <1% of non-TBI. We characterized the Lymphosarcoma into the following groups based on the St. Jude pathology subclassification: Diffuse Lymphosarcoma involving multiple organs, Thymic lymphoma (usually associated with thymic and around the heart), Lymphosarcoma (potentially starting in the spleen and peri-pancreatic lymph nodes (Ab=abdomen)), and follicular lymphoma seen as a diffuse proliferation of lymphocytes in the white pulp area in the spleen. Thymic lymphomas were the most common, followed by Lymphosarcoma (Ab), follicular lymphoma (restricted to white pulp area in the spleen) and diffuse Lymphosarcoma. Immunostain markers revealed the thymic lymphomas were from T-cell lineage and the abdominal Lymphosarcoma were mainly from B-cell lineage. A few mice had disease involving the bone marrow. Taken together, these data suggest that the increased cycling among primitive hematopoietic cells in survivors of lethal radiation may contribute to stem cell exhaustion and subsequent RBMD, as well as predispose survivors to hematopoietic neoplasias.Item Interleukin-1α Promotes Tumor Growth and Cachexia in MCF-7 Xenograft Model of Breast Cancer(Elsevier, 2003-12) Kumar, Suresh; Kishimoto, Hiromitsu; Chua, Hui Lin; Badve, Sunil; Miller, Kathy D.; Bigsby, Robert M.; Nakshatri, HarikrishnaProgression of breast cancer involves cross-talk between epithelial and stromal cells. This cross-talk is mediated by growth factors and cytokines secreted by both cancer and stromal cells. We previously reported expression of interleukin (IL)-1α in a subset of breast cancers and demonstrated that IL-1α is an autocrine and paracrine inducer of prometastatic genes in in vitro systems. To understand the role of IL-1α in breast cancer progression in vivo, we studied the growth of MCF-7 breast cancer cells overexpressing a secreted form of IL-1α (MCF-7IL-1α) in nude mice. MCF-7IL-1α cells formed rapidly growing estrogen-dependent tumors compared to parental cells. Interestingly, IL-1α expression alone was not sufficient for metastasis in vivo although in vitro studies showed induction of several prometastatic genes and matrix metalloproteinase activity in response to cross-talk between IL-1α-expressing cancer cells and fibroblasts. Animals implanted with MCF-7IL-1α cells were cachetic, which correlated with increased leptin serum levels but not other known cachexia-inducing cytokines such as IL-6, tumor necrosis factor, or interferon gamma. Serum triglycerides, but not blood glucose were lower in animals with MCF-7IL-1α cell-derived tumors compared to animals with control cell-derived tumors. Cachexia was associated with atrophy of epidermal and adnexal structures of skin; a similar phenotype is reported in triglyceride-deficient mice and in ob/ob mice injected with leptin. Mouse leptin-specific transcripts could be detected only in MCF-7IL-1α cell-derived tumors, which suggests that IL-1α increases leptin expression in stromal cells recruited into the tumor microenvironment. Despite increased serum leptin levels, animals with MCF-7IL-1α cell-derived tumors were not anorexic suggesting only peripheral action of tumor-derived leptin, which principally targets lipid metabolism. Taken together, these results suggest that cancer cell-derived cytokines, such as IL-1α, induce cachexia by affecting leptin-dependent metabolic pathways.