Complementary Lipidomic, Proteomic, and Mass Spectrometry Imaging Approach to the Characterization of the Acute Effects of Radiation in the Non-human Primate Mesenteric Lymph Node after Partial-body Irradiation with Minimal Bone Marrow Sparing

Abstract

Radiation sequelae is complex and characterized by multiple pathologies, which occur over time and nonuniformly throughout different organs. The study of the mesenteric lymph node (MLN) due to its importance in the gastrointestinal system is of particular interest. Other studies have shown an immediate post-irradiation reduction in cellularity due to the known effects of irradiation on lymphoid cell populations, but the molecular and functional mechanisms that lead to these cellular alterations remain limited. In this work, we show the use of lipidomic, proteomic, and mass spectrometry imaging in the characterization of the effects of acute radiation exposure on the MLN at different time points after ionizing radiation (IR) from 4 d to 21 d after 12 Gy partial body irradiation with 2.5% bone marrow sparing. The combined analyses showed a dysregulation of the lipid and protein composition in the MLN after IR. Protein expression was affected in numerous pathways, including pathways regulating lipids such as LXR/RXR activation and acute phase response. Lipid distribution and abundance was also affected by IR in the MLN, including an accumulation of triacylglycerides, a decrease in polyunsaturated glycerophospholipids, and changes in polyunsaturated fatty acids. Those changes were observed as early as 4 d after IR and were more pronounced for lipids with a higher concentration in the nodules and the medulla of the MLN. These results provide molecular insight into the MLN that can inform on injury mechanism in a non-human primate model of the acute radiation syndrome of the gastrointestinal tract. Those findings may contribute to the identification of therapeutic targets and the development of new medical countermeasures.

Acute Proteomic Changes in Lung after Radiation: Toward Identifying Initiating Events of Delayed Effects of Acute Radiation Exposure in Non-human Primate after Partial Body Irradiation with Minimal Bone Marrow Sparing

“…FXR agonism has been shown to decrease fibrosis in multiple animal models (Libby et al 2021). In addition to lung, acute phase response signaling is a canonical pathway identified as dysregulated in heart, kidney, lymph node, jejunum, and plasma (Huang et al 2020a; Huang et al 2020b; Muller et al 2021; Zalesak et al 2021; Huang et al 2021).…”

Animal Models: A Non-human Primate and Rodent Animal Model Research Platform, Natural History, and Biomarkers to Predict Clinical Outcome

“…A systems biology approach allows for an unbiased assessment of the natural history of acute and delayed effects of radiation injury on the molecular level. Thorough analyses of NHP PBI/BM-sparing models using omics-based methods has provided a more complete understanding of natural history on the molecular level defining quantifiable molecules with biomarker potential (Jones et al 2015a; Carter et al 2019; Huang et al 2020a and b, 2021a and b; Kumar et al 2020, 2021; Muller et al 2021; Yu et al 2021; Zalesak-Kravec et al 2021). Similar approaches in other NHP exposure models (whole thorax lung irradiation, TBI) (Carter et al 2015, 2017; Jones et al 2015a) as well as mouse models (Jones et al 2015b, 2017a, 2019a and b; Huang et al 2019a and b) are useful toward providing additional evidentiary support for biomarker utility.…”