Acute Gastrointestinal Syndrome in High-Dose Irradiated Mice

Abstract

The most detailed reports of the response of the gastrointestinal system to high dose acute radiation have focused mainly on understanding the histopathology. However, to enable medical countermeasure assessment under the animal rule criteria, it is necessary to have a robust model in which the relationship between radiation dose and intestinal radiation syndrome incidence, timing and severity are established and correlated with histopathology. Although many mortality studies have been published, they have used a variety of mouse strains, ages, radiation sources and husbandry conditions, all of which influence the dose response. Further, it is clear that the level of bone marrow irradiation and supportive care can influence endpoints. In order to create robust baseline data we have generated dose response data in adult male mice, maintained under identical conditions, and exposed to either total or partial-body irradiation. Partial-body irradiation includes both extensive (40%) and minimal (5%) bone marrow sparing models, the latter designed to correlate with an established primate model and allow assessment of effects of any medical countermeasure on all three major radiation syndromes (intestinal, bone marrow and lung) in the surviving mice. Lethal dose (LD30, LD50 and LD70) data are described in the various models, along with the impact of enteric flora and response to supportive care. Correlation with diarrhea severity and histopathology are also described. This data can be used to aid the design of good laboratory practice (GLP) compliant Animal Rule studies that are reflective of the conditions following accidental radiation exposure.

Indoles from commensal bacteria extend healthspan

“…In the context of aging, epithelial barrier integrity is important in limiting dissemination of bacterial products (42,43), and the subsequent hyperinflammatory responses that can cause widespread tissue damage, a process termed "inflammaging" (44,45). Barrier integrity limits enteritis and extends survival following TBI (46,47). Whether augmenting intestinal barrier integrity or systemic antiinflammatory effects contribute to indole effects on healthspan and motility in geriatric animals is currently under investigation.…”

The MCART Consortium Animal Model Series

“…These recommendations underscore the requirement for valid animal models with established DRRs for mortality and morbidity that will likely be modified due to use of medical management (Farese et al 2012a and b;MacVittie et al 2012a and b;Booth et al 2012b;Plett et al 2012). It is important to link the respective animal models (i.e., mouse and NHP) for organ-specific damage in the ARS or DEARE relative to the type of supportive care and concept of operations for the medical management of irradiated personnel.…”

“…The trigger-based administration of medical management can be "population-based," as for mouse studies, or "patient-based" for studies using NHP. There is a significant preclinical database supporting the use and timing of effective medical management in mice, canines, and NHP (MacVittie et al 1991(MacVittie et al , 2001Sorensen et al 1960;Booth et al 2012b;Farese et al 2012a;Plett et al 2012;Garofalo et al 2014;MacVittie 2012MacVittie , 2014. All supportive care measures are adapted from consensus-based clinical standards of treatment (Waselenko et al 2004;Schimpff 1990;Hughes 2002;Gafter-Gvili et al 2005;Freifeld et al 2011;Fliedner et al 2001).…”

The MCART Consortium Animal Models Series

“…Confounding variables (e.g., radiation physics, supportive care, vendors, mouse strain, chronosensitivity, etc. that affect animal model development) must be considered Booth et al 2012b;Jackson et al 2012); b) Predictive validity is paramount since it indicates that the performance of the animal model in a test or screening assay for MCM efficacy is predictive of the performance in a higher species; i.e. the human exposed to a potentially lethal dose of radiation.…”