scholarly journals Effects of captopril against radiation injuries in the Göttingen minipig model of hematopoietic-acute radiation syndrome

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256208
Author(s):  
W. Bradley Rittase ◽  
Elizabeth A. McCart ◽  
Jeannie M. Muir ◽  
Roxane M. Bouten ◽  
John E. Slaven ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Total Body Irradiation ◽  
Blood Cells ◽  
Acute Radiation ◽  
Radiation Injuries ◽  
Induced Expression ◽  
Acute Radiation Syndrome ◽  
Radiation Induced ◽  
Total Body ◽  
Captopril Treatment

Our laboratory has demonstrated that captopril, an angiotensin converting enzyme inhibitor, mitigates hematopoietic injury following total body irradiation in mice. Improved survival in mice is correlated with improved recovery of mature blood cells and bone marrow, reduction of radiation-induced inflammation, and suppression of radiation coagulopathy. Here we investigated the effects of captopril treatment against radiation injuries in the Göttingen mini pig model of Hematopoietic-Acute Radiation Syndrome (H-ARS). Minipigs were given captopril orally (0.96 mg/kg) twice daily for 12 days following total body irradiation (60Co 1.79 Gy, 0.42–0.48 Gy/min). Blood was drawn over a time course following irradiation, and tissue samples were collected at euthanasia (32–35 days post-irradiation). We observed improved survival with captopril treatment, with survival rates of 62.5% in vehicle treated and 87.5% in captopril treated group. Additionally, captopril significantly improved recovery of peripheral blood mononuclear cells, and a trend toward improvement in recovery of red blood cells and platelets. Captopril significantly reduced radiation-induced expression of cytokines erythropoietin and granulocyte-macrophage colony-stimulating factor and suppressed radiation-induced acute-phase inflammatory response cytokine serum amyloid protein A. Using quantitative-RT-PCR to monitor bone marrow recovery, we observed significant suppression of radiation-induced expression of redox stress genes and improved hematopoietic cytokine expression. Our findings suggest that captopril activities in the Göttingen minipig model of hematopoietic-acute radiation syndrome reflect findings in the murine model.

Pulmonary toxicity following total body irradiation for acute lymphoblastic leukaemia: The Ottawa Hospital Cancer Centre (TOHCC) experience

2015 ◽  
Vol 15 (1) ◽  
pp. 54-60
Author(s):  
R. K. Ujaimi ◽  
N. Isfahanian ◽  
D. J. La Russa ◽  
R. Samant ◽  
C. Bredeson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Total Body Irradiation ◽  
Pulmonary Toxicity ◽  
Conditioning Regimen ◽  
Cancer Centre ◽  
Ottawa Hospital ◽  
Radiation Induced ◽  
Total Body

AbstractPurposeTo review the incidence of clinically significant pulmonary toxicity following total body irradiation (TBI) as a part of the conditioning regimen for acute lymphoblastic leukaemia (ALL) patients undergoing bone marrow transplantation (BMT) at The Ottawa Hospital Cancer Centre.MethodsThis is a retrospective review of ALL patients who received TBI in The Ottawa Hospital Bone Marrow Transplant Program (TOH-BMT) as part of their conditioning regimen from 1991 to 2011 inclusive. The patients were treated using a locally developed translating-couch irradiation technique. We have analysed all available data for the first 100 days following TBI to determine the incidence of radiation-induced pulmonary toxicities.ResultsOf the total 622 patients undergoing TBI during the specified period, 88 had ALL. Median age at BMT was 30 years and the conditioning regimens varied. A total of 74 (84%) patients received 12 Gy/6 F/BID of TBI. A total of 55 (63%) patients have died, 32 (36%) within the 1st year after BMT. In the 1st year, pulmonary events were reported for 24 (27%) patients, and the follow-up notes were unavailable for seven (8%). Pulmonary toxicities were reported as the cause of death for six patients, five (6%) within the 1st year. It is estimated that the total number of deaths in the 1st year possibly attributed to radiation-induced lung injury was four (4·5%). Eight (9%) patients had symptoms suggestive of non-lethal grade 2–3 radiation-induced pneumonitis.ConclusionsTBI continues to be an important component of the conditioning regimen for ALL patients undergoing BMT, and the incidence of radiation-induced pulmonary injury, using our technique and lung dose, is comparable to the published literature.

scholarly journals Mechanism and therapeutic window of a genistein nanosuspension to protect against hematopoietic-acute radiation syndrome

2019 ◽  
Vol 60 (3) ◽  
pp. 308-317 ◽  
Author(s):  
Michael R Landauer ◽  
Adam J Harvey ◽  
Michael D Kaytor ◽  
Regina M Day
Keyword(s):  
Estrogen Receptor ◽  
Mechanism Of Action ◽  
Total Body Irradiation ◽  
Intramuscular Injection ◽  
Acute Radiation ◽  
Beta Agonist ◽  
Therapeutic Window ◽  
Acute Radiation Syndrome ◽  
Single Intramuscular Injection ◽  
Total Body

Abstract There are no FDA-approved drugs that can be administered prior to ionizing radiation exposure to prevent hematopoietic–acute radiation syndrome (H-ARS). A suspension of synthetic genistein nanoparticles was previously shown to be an effective radioprotectant against H-ARS when administered prior to exposure to a lethal dose of total body radiation. Here we aimed to determine the time to protection and the duration of protection when the genistein nanosuspension was administered by intramuscular injection, and we also investigated the drug’s mechanism of action. A single intramuscular injection of the genistein nanosuspension was an effective radioprotectant when given prophylactically 48 h to 12 h before irradiation, with maximum effectiveness occurring when administered 24 h before. No survival advantage was observed in animals administered only a single dose of drug after irradiation. The dose reduction factor of the genistein nanosuspension was determined by comparing the survival of treated and untreated animals following different doses of total body irradiation. As genistein is a selective estrogen receptor beta agonist, we also explored whether this was a central component of its radioprotective mechanism of action. Mice that received an intramuscular injection of an estrogen receptor antagonist (ICI 182,780) prior to administration of the genistein nanosuspension had significantly lower survival following total body irradiation compared with animals only receiving the nanosuspension (P < 0.01). These data define the time to and duration of radioprotection following a single intramuscular injection of the genistein nanosuspension and identify its likely mechanism of action.

scholarly journals Cholinergic and cytoprotective signaling cascades mediate the mitigative effect of erythropoietin on acute radiation syndrome

2018 ◽  
Vol 96 (5) ◽  
pp. 442-458
Author(s):  
Shereen Mohamed Galal ◽  
Mohamed Khairy Abdel-Rafei ◽  
Hesham Farouk Hasan
Keyword(s):  
White Blood Cells ◽  
Acute Radiation ◽  
Janus Kinase ◽  
Sublethal Dose ◽  
Related Factor ◽  
Acute Radiation Syndrome ◽  
Signal Transducers ◽  
Human Erythropoietin ◽  
Radiation Induced ◽  
Total Body

The present investigation aimed to evaluate the radiomitigative efficacy of the recombinant human erythropoietin (EPO) against acute radiation syndrome (ARS) in a rat model. Rats were irradiated with a single sublethal dose of γ-radiation (7 Gy; total body irradiation; TBI) on the 1st day of experimental course, then received EPO (5000 IU/kg; i.p.) 24 h after irradiation, and rats were observed for 30 days of survival analysis. Administration of EPO improved 30-day survival, alleviated TBI-induced myelosuppression and pancytopenia, by augmenting lymphocytes and other white blood cells in the peripheral blood of rats, while bone marrow and spleen cellularity were restored. EPO post-exposure treatment alleviated hepatotoxicity biomarkers and restored splenic function. EPO abrogated radiation-induced oxidative stress through the upregulation of the cholinergic anti-inflammatory nicotinic acetylcholine receptor (α-7-nAChR) and the pro-survival Janus kinase-2 and signal transducers and activators of transcription JAK-2/STAT-3 signaling mediated via enhancing nuclear factor erythroid-2 related factor-2 (Nrf-2) cytoprotective machinery in liver and spleen of irradiated rats. Moreover, EPO treatment prevented hepatic and splenic apoptosis. The present study establishes the implication of α-7-nAChR–JAK-2/STAT-3–Nrf-2 signaling cascade in the radiomitigative potential of EPO against ARS.

scholarly journals Proteomic Evaluation of the Acute Radiation Syndrome of the Gastrointestinal Tract in a Murine Total-body Irradiation Model

2019 ◽  
Vol 116 (4) ◽  
pp. 516-528 ◽  
Author(s):  
Weiliang Huang ◽  
Jianshi Yu ◽  
Jace W. Jones ◽  
Claire L. Carter ◽  
Keely Pierzchalski ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Total Body Irradiation ◽  
Acute Radiation ◽  
Acute Radiation Syndrome ◽  
Total Body

Acute Radiation Syndrome Severity Score System in Mouse Total-Body Irradiation Model

2016 ◽  
Vol 111 (2) ◽  
pp. 134-144 ◽  
Author(s):  
Natalia I. Ossetrova ◽  
Patrick H. Ney ◽  
Donald P. Condliffe ◽  
Katya Krasnopolsky ◽  
Kevin P. Hieber
Keyword(s):  
Total Body Irradiation ◽  
Severity Score ◽  
Acute Radiation ◽  
Score System ◽  
Acute Radiation Syndrome ◽  
Total Body

scholarly journals Nonhuman Primates with Acute Radiation Syndrome: Results from a Global Serum Metabolomics Study after 7.2 Gy Total-Body Irradiation

2018 ◽  
Vol 190 (6) ◽  
pp. 576 ◽  
Author(s):  
Evan L. Pannkuk ◽  
Evagelia C. Laiakis ◽  
Melissa Garcia ◽  
Albert J. Fornace ◽  
Vijay K. Singh
Keyword(s):  
Total Body Irradiation ◽  
Nonhuman Primates ◽  
Acute Radiation ◽  
Acute Radiation Syndrome ◽  
Metabolomics Study ◽  
Total Body ◽  
Serum Metabolomics

5-Androstene-3b,17b-Diol Administration of Mice Exposed to Total Body Irradiation Results in Rapid Reconstitution of Immature Bone Marrow Progenitor Cells and Synergizes with Thrombopoietin but Not with Granulocyte-Colony Stimulating Factor.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2327-2327
Author(s):  
Fatima SF Aerts Kaya ◽  
Trudi P Visser ◽  
James M Frincke ◽  
Dwight R. Stickney ◽  
Chris L Reading ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Total Body Irradiation ◽  
Blood Cells ◽  
Fold Increase ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Total Body ◽  
Marrow Cellularity ◽  
Immature Cells ◽  
Stimulating Factor

Abstract 5-AED (5-androstene-3β,17β-diol) is a naturally occurring adrenal cortical steroid, which displays radioprotective effects in both rodents and non-human primates, resulting in accelerated multilineage hematopoiesis and enhanced survival after total body irradiation (TBI), including a 1-log accelerated CD34+ cell reconstitution in bone marrow of non-human primates. Pegylated granulocyte-colony stimulating factor (Peg-G-CSF) is known to stimulate lineage-specific recovery of neutrophils, whereas the effects of thrombopoietin (TPO) are broader and include protection of short-term spleen repopulating immature cells as well as platelet recovery. To gain insight into the mechanism of 5-AED on immature hematopoietic cells, the effects of 5-AED on multilineage hematopoiesis and recovery of specific repopulating stem and progenitor cell subsets after TBI was evaluated in combination with and relative to either Peg-G-CSF or TPO. For direct measurements of the radioprotective effect of 5-AED, BALB/c mice were exposed to a midlethal dose of 6 Gy TBI. Two hours after TBI, mice were injected IM with 40 mg/kg 5-AED or the carrier, with or without 0.225 mg TPO or 10 mg Peg-G-CSF IP. Radioprotective effects of 5-AED on immature repopulating cell subsets were assessed by exposing BALB/c donor mice to 3 fractions of 2 Gy TBI, separated by 24 hours, and treatment with 40 mg/kg/d 5-AED or the carrier IM, or 0.7 mg TPO IP after each fraction or a single injection of 10 mg Peg-G-CSF IP after the first fraction. Twenty four hours after the last fraction, bone marrow of donor mice was examined for immature cell content per femur using the marrow repopulating ability (MRA day 13) assay and the CFU-S day 12 after transplantation in 8 Gy irradiated mice. After 6 Gy TBI, BALB/c mice treated with 5-AED displayed an accelerated multilineage recovery with increased white blood cells (p&lt;0.001), blood platelets (p&lt;0.0001) and red blood cells (p&lt;0.03), as well as increased bone marrow cellularity (p&lt;0.0001) and elevated numbers of bone marrow colony forming cells (p&lt;0.00001) at 14 days post-TBI in comparison to placebo-treated animals. Increasing the 5-AED dose up to 200 mg/kg did not augment this effect. Combined treatment with 5-AED and Peg-G-CSF or TPO treatment did not result in an additive effect in this setting. However, after the fractionated 3x2 Gy, a 5- and 7- fold increase in CFU-S relative to radiation controls was observed in the 5-AED and TPO groups, respectively, and a synergistic 20-fold increase in CFU-S day 12 was observed when 5-AED and TPO were used simultaneously. Consistent with earlier observations, Peg-GCSF alone did not affect CFU-S day 12 and appeared to dampen the effect of 5-AED. MRA, expressed as GM-CFU per femur at 13 days after transplantation, was found to be increased 5- to 6-fold with 1002 colonies (range 0-5785) for 5-AED versus 174 (5-360) for radiation controls. This is in contrast to TPO, which promotes CFU-S reconstitution at the expense of the more immature MRA (Neelis et al. 1998: Blood92, 1586). Thus, 5-AED as a single agent stimulates multilineage hematopoiesis and increases bone marrow cellularity following TBI. This effect is mediated by increased survival and/or reconstitution of immature repopulating cells in a pattern distinct from that of TPO. Consistently, 5-AED strongly synergizes with TPO at the level of immature cells from which reconstitution originates, thus revealing a novel mechanism of bone marrow protection in cytoreductive therapy.

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