Experimental Quantification of Delayed Radiation-Induced Organ Damage in Highly Irradiated Rats With Bone Marrow Protection

Boittin, François-Xavier; Martigne, P.; Mayol, Jean-François; Denis, Jean‐Noël; Florent, R; Coulon, David; Grenier, Nancy; Drouet, M.; Hérodin, Françis

doi:10.1097/hp.0000000000000300

Cited by 6 publications

(4 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar to our studies, Booth et al also observed long-term damage to the murine intestine, including microadenomas, thicker submucosa, shorter crypts and villi, and increased collagen, extending 125 to 200 days post-PBI with 40% bone marrow shielding (9). In Wistar rats that received 12 Gy and 14 Gy irradiation with approximately 20% bone marrow sparing also showed decreased villus height even after 64 and 104 days postirradiation (36). In total, these findings indicate that PBI can exert long-lasting mucosal damage in animals irrespective of species.…”

Section: Discussionsupporting

confidence: 90%

Differential Recovery of Small Intestinal Segments after Partial-Body Irradiation in Non-Human Primates

Wang¹,

Garg²,

Landes

et al. 2021

Radiation Research

View full text Add to dashboard Cite

In the event of a radiological attack or accident, it is more likely that the absorbed radiation dose will be heterogeneous, rather than uniformly distributed throughout the body. This type of uneven dose distribution is known as partial-body irradiation (PBI). Partial exposure of the vital organs, specifically the highly radiosensitive intestines, may cause death, if the injury is significant and the post-exposure recovery is considerably compromised. Here we investigated the recovery rate and extent of recovery from PBI-induced intestinal damage in large animals. Rhesus macaques (Macaca mulatta) were randomly divided into four groups: sham-irradiated (0 Gy), 8 Gy PBI, 11 Gy PBI and 14 Gy PBI. A single dose of ionizing radiation was delivered in the abdominal region using a uniform bilateral anteroposterior and posteroanterior technique. Irradiated animals were scheduled for euthanasia on days 10, 28 or 60 postirradiation, and sham-irradiated animals on day 60. Intestinal structural injuries were assessed via crypt depth, villus height, and mucosal surface length in the four different intestinal regions (duodenum, proximal jejunum, distal jejunum and ileum) using H&E staining. Higher radiation doses corresponded with more injury at 10 days post-PBI and a faster recovery rate. However, at 60 days post-PBI, damage was still evident in all regions of the intestine. The proximal and distal ends (duodenum and ileum, respectively) sustained less damage and recovered more fully than the jejunum.

show abstract

Section: Discussionsupporting

confidence: 90%

Differential Recovery of Small Intestinal Segments after Partial-Body Irradiation in Non-Human Primates

Wang¹,

Garg²,

Landes

et al. 2021

Radiation Research

View full text Add to dashboard Cite

show abstract

“…However, the primate studies were done without bone marrow sparing and therefore involved much lower doses of irradiation (<10 Gy). A study with male Wistar rats irradiated with 12 or 14 Gy PBI with both hind legs shielded (Boittin et al 2015), supports the role of antibiotics for enhancing survival. That group detected bacterial infection in blood cultured pre-mortem following 14 Gy, in which rats not given Enrofloxacin died by 10 days, probably due to bacterial translocation from GI injury.…”

Section: Discussionmentioning

confidence: 84%

Combined Hydration and Antibiotics with Lisinopril to Mitigate Acute and Delayed High-dose Radiation Injuries to Multiple Organs

et al. 2016

View full text Add to dashboard Cite

The NIAID Radiation and Nuclear Countermeasures Program is developing medical agents to mitigate the acute and delayed effects of radiation that may occur from a radionuclear attack or accident. To date, most such medical countermeasures have been developed for single organ injuries. Angiotensin converting enzyme (ACE) inhibitors have been used to mitigate radiation-induced lung, skin, brain and renal injuries in rats. ACE inhibitors have also been reported to decrease normal tissue complication in radiation oncology patients. In the current study we have developed a rat partial-body irradiation (leg-out PBI) model with minimal bone marrow sparing (one leg shielded) that results in acute and late injuries to multiple organs. In this model, the ACE inhibitor lisinopril (at ∼24 mg m-2 day-1 started orally in the drinking water at 7 days after irradiation and continued to ≥150 days) mitigated late effects in the lungs and kidneys after 12.5 Gy leg-out PBI. Also in this model, a short course of saline hydration and antibiotics mitigated acute radiation syndrome following doses as high as 13 Gy. Combining this supportive care with the lisinopril regimen mitigated overall morbidity for up to 150 days after 13 Gy leg-out PBI. Furthermore lisinopril was an effective mitigator in the presence of the growth factor G-CSF (100 μg kg-1 day-1 from days 1-14) which is FDA-approved for use in a radionuclear event. In summary, by combining lisinopril (FDA-approved for other indications) with hydration and antibiotics, we mitigated acute and delayed radiation injuries in multiple organs.

show abstract

“…The ability of surviving BM hematopoietic progenitor cells (HPC), either localized to a marrow site or dispersed throughout the total marrow space, to accelerate hematopoietic recovery after highly myelosuppressive irradiation has been consistent and is model independent, be it partial-body with marrow shielding/sparing, or unilateral, non-uniform total-body exposure in several animal species (Maillie et al 1966;Cole et al 1967;Wise and Turbyfill 1968;Gidali and Lajtha 1972;Maloney and Patt 1972;Monroy et al 1988;Wang et al 1991;Geraci et al 1992;Bertho et al 2005a;Booth et al 2012;Herodin et al 2012;MacVittie et al 2012a;Drouet et al 2014;Boittin et al 2015). The critical condition is the differential dose distribution throughout the tissue and the basic assumptions that hematopoietic recovery from the H-ARS is dependent on the survival of a critical fraction of HPC that are equally distributed throughout the active marrow tissue, independent of location and equivalent in regenerative ability (Bond and Robinson 1967;Taketa et al 1970;Bond et al 1991;Campbell et al 2015).…”

Section: Discussionmentioning

confidence: 99%

“…These conditions forecast the sparing of variable amounts of critical organ tissue that will define the severity of the ARS and DEARE. The sparing of BM, GI, lung, heart and/or kidney tissue, can have dramatic effects on the incidence, latency, severity, progression and resolution of organ-specific and organ-interactive sequelae (Ainsworth et al 1965;Cole et al 1967;Wise and Turbyfill 1968;Rauchwerger 1972;Monroy et al 1988;Mason et al 1989;Terry and Travis 1989;Geraci et al 1990;Guskova et al 1990;Geraci et al 1992;Liao et al 1995;Bertho et al 2005a;Novakova-Jiresova et al 2005;van Luijk et al 2007;Drouet et al 2008;Granton et al 2014;Boittin et al 2015). Non-uniform and/or heterogeneous exposure with or without medical management will change the organ-specific dose response relationships (DRR) for morbidity and mortality throughout the ARS and DEARE (Ainsworth et al 1965;Wise and Turbyfill 1968;Evans et al 1987;Baranov and Guskova 1990;Guskova et al 1990;Herodin et al 2007;MacVittie et al 2012a).…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Neulasta or Neupogen on H-ARS and GI-ARS Mortality and Hematopoietic Recovery in Nonhuman Primates After 10-Gy Irradiation With 2.5% Bone Marrow Sparing

et al. 2019

View full text Add to dashboard Cite

A nonhuman primate (NHP) model of acute, partial-body, high dose, irradiation with minimal (2.5%) bone marrow sparing (PBI/BM2.5) was used to assess the endogenous gastrointestinal and hematopoietic recovery and the ability of Neulasta ® (pegylated granulocyte colony stimulating factor [G-CSF]) or Neupogen ® (G-CSF) to enhance recovery from myelosuppression when administered at an increased interval between exposure and initiation of treatment. A secondary objective was to assess the effect of Neulasta ® or Neupogen ® on the mortality and morbidity due to the hematopoietic acute radiation syndrome (H-ARS) and concomitant acute gastrointestinal (GI)-ARS. NHP were exposed to 10.0 Gy 6 megavolt (MV) linear accelerator (LINAC)-derived photons delivered at 0.80 Gy min −1 . All NHP received subject-based medical management. NHP were dosed daily with control article (5% dextrose in water) initiated on day 1 post-exposure, or Neulasta ® (300 μg kg −1 ) administered on days 1 and 8 or days 3 and 10 post-exposure, or Neupogen ® (10 μg kg −1 ) administered daily post-exposure following its initiation on day 1 or day 3 until neutrophil recovery (absolute neutrophil count [ANC] ≥ 1,000 cells μL −1 for 3 consecutive days). Mortality in the irradiated-cohorts suggested that administration of Neulasta ® or Neupogen ® at either schedule did not affect mortality due to acute GI-ARS or mitigate mortality due to H-ARS (plus GI damage). Following 10.0 Gy PBI/BM2.5, the mean duration of neutropenia (absolute neutrophil count < 500 cells μL −1 ) was 22.4 days in the control cohort, versus 13.0 and 15.3 days in the Neulasta ® day 1-8 and day 3-10 cohorts relative to 16.2 and 17.4 days in the Neupogen ® cohorts initiated on day 1 and day 3, respectively. The absolute neutrophil count nadirs were 48 cells μL −1 in the controls, 117 cells μL −1 and 40 cells μL −1 in the Neulasta ® days 1, 8 and days 3, 10 cohorts, respectively, and 75 cells μL −1 , and 37 cells μL −1 in the Neupogen ® day 1 and day 3 cohorts, respectively. Therefore, the earlier administration of Neulasta ® or Neupogen ® was more effective in this model of marginal 2.5% BM sparing. The approximate 2.5% BM-sparing may approximate the threshold for efficacy of the lineage-specifc

show abstract

Experimental Quantification of Delayed Radiation-Induced Organ Damage in Highly Irradiated Rats With Bone Marrow Protection

Cited by 6 publications

References 26 publications

Differential Recovery of Small Intestinal Segments after Partial-Body Irradiation in Non-Human Primates

Differential Recovery of Small Intestinal Segments after Partial-Body Irradiation in Non-Human Primates

Combined Hydration and Antibiotics with Lisinopril to Mitigate Acute and Delayed High-dose Radiation Injuries to Multiple Organs

Efficacy of Neulasta or Neupogen on H-ARS and GI-ARS Mortality and Hematopoietic Recovery in Nonhuman Primates After 10-Gy Irradiation With 2.5% Bone Marrow Sparing

Contact Info

Product

Resources

About