Mechanisms Involved in the Development of the Chronic Gastrointestinal Syndrome in Nonhuman Primates after Total-Body Irradiation with Bone Marrow Shielding

Abstract

In this study, nonhuman primates (NHPs) exposed to lethal doses of total body irradiation (TBI) within the gastrointestinal (GI) acute radiation syndrome range, sparing ~5% of bone marrow (TBI-BM5), were used to evaluate the mechanisms involved in development of the chronic GI syndrome. TBI increased mucosal permeability in the jejunum (12–14 Gy) and proximal colon (13–14 Gy). TBI-BM5 also impaired mucosal barrier function at doses ranging from 10–12.5 Gy in both small intestine and colon. Timed necropsies of NHPs at 6–180 days after 10 Gy TBI-BM5 showed that changes in small intestine preceded those in the colon. Chronic GI syndrome in NHPs is characterized by continued weight loss and intermittent GI syndrome symptoms. There was a long-lasting decrease in jejunal glucose absorption coincident with reduced expression of the sodium-linked glucose transporter. The small intestine and colon showed a modest upregulation of several different pro-inflammatory mediators such as NOS-2. The persistent inflammation in the post-TBI-BM5 period was associated with a long-lasting impairment of mucosal restitution and a reduced expression of intestinal and serum levels of alkaline phosphatase (ALP). Mucosal healing in the postirradiation period is dependent on sparing of stem cell crypts and maturation of crypt cells into appropriate phenotypes. At 30 days after 10 Gy TBI-BM5, there was a significant downregulation in the gene and protein expression of the stem cell marker Lgr5 but no change in the gene expression of enterocyte or enteroendocrine lineage markers. These data indicate that even a threshold dose of 10 Gy TBI-BM5 induces a persistent impairment of both mucosal barrier function and restitution in the GI tract and that ALP may serve as a biomarker for these events. These findings have important therapeutic implications for the design of medical countermeasures.

A New Zealand White rabbit model of thrombocytopenia and coagulopathy following total body irradiation across the dose range to induce the hematopoietic-subsyndrome of acute radiation syndrome

“…Microscopic exam of the small and large intestine showed pathologic features consistent with the gastrointestinal-subsyndrome of ARS. Across all radiation doses, there was more damage to the small intestine than the colon, which is consistent with that previously observed in the non-human primate (MacVittie et al 2012;Shea-Donohue et al 2016). While the increase in blood urea nitrogen levels at the time of unscheduled euthanasia was suggestive of acute renal failure, microscopic exam showed only scatted tubular injury in animals exposed to doses of 7.5 Gy or higher.…”

Gene expression analyses of the small intestine of pigs in the ex-evacuation zone of the Fukushima Daiichi Nuclear Power Plant

“…The elevations of IFN-γ and TLR3 in pigs from the ex-evacuation zone might not be regulated by the same mechanism. A previous study by Shea-Donohue et al investigated the influence of radiation on the cytokine balance in the small intestine and colon in non-human primates and demonstrated an increase in the gene expression of inflammatory cytokines, such as IFN-γ , after irradiation [ 24 ]. These findings suggest that radiation exposure might result in the alteration of immune genes in animals in the ex-evacuation zone.…”

Loss of immune homeostasis dictates SHIV rebound after stem-cell transplantation

“…Total body irradiation/myeloablative conditioning results in many changes including lymphocyte depletion and damage to secondary lymphoid tissues such as the gastrointestinal (GI) tract (15)(16)(17). Here we defined the immunological mechanisms at play in SHIV-infected, cART-suppressed macaques following autologous transplantation in our well-established SHIV model.…”