Cardiac and Renal Delayed Effects of Acute Radiation Exposure: Organ Differences in Vasculopathy, Inflammation, Senescence and Oxidative Balance

Abstract

We have previously shown significant pathology in the heart and kidney of murine hematopoietic-acute radiation syndrome (H-ARS) survivors of 8.7-9.0 Gy total-body irradiation (TBI). The goal of this study was to determine temporal relationships in the development of vasculopathy and the progression of renal and cardiovascular delayed effects of acute radiation exposure (DEARE) at TBI doses less than 9 Gy and to elucidate the potential roles of senescence, inflammation and oxidative stress. Our results show significant loss of endothelial cells in coronary arteries by 4 months post-TBI (8.53 or 8.72 Gy of gamma radiation). This loss precedes renal dysfunction and interstitial fibrosis and progresses to abnormalities in the arterial media and adventitia and loss of coronary arterioles. Major differences in radiation-induced pathobiology exist between the heart and kidney in terms of vasculopathy progression and also in indices of inflammation, senescence and oxidative imbalance. The results of this work suggest a need for different medical countermeasures for multiple targets in different organs and at various times after acute radiation injury to prevent the progression of DEARE.

Immune Reconstitution and Thymic Involution in the Acute and Delayed Hematopoietic Radiation Syndromes

“…All tissues were harvested following euthanasia by CO 2 or isoflurane inhalation, as previously described (Unthank et al 2015, Unthank et al 2019. Thymi were carefully cleared of fat and connective tissue under a dissecting microscope to eliminate contamination with non-thymic tissue.…”

“…The authors have previously developed a well-characterized murine model of H-ARS and DEARE in young adult C57BL/6 mice, and have used this model to study mechanisms and efficacy of MCM against radiation for licensure and treatment strategies (Plett et al 2012, Shakhov et al 2012, Hoggatt et al 2013, Garrett et al 2014, Unthank et al 2015, Fish et al 2016, Dynlacht et al 2017, Garrett et al 2019, Jones et al 2019, Unthank et al 2019. Herein, the authors have characterized the prolonged immunosuppression at all levels of lymphocyte development in these acute and chronic radiation models.…”

A Potential Role for Excess Tissue Iron in Development of Cardiovascular Delayed Effects of Acute Radiation Exposure

“…Vascular injury may be a mechanism for delayed radiation-induced tissue injury (Fajardo and Berthrong 1988), but few studies have addressed DEARE at doses where survival from ARS is a possibility, i.e., less than 10 Gy. Recent results (Unthank et al 2019) indicate that heart vessel endothelial cell loss occurs before 4 months post-total body irradiation (TBI) in the H-ARS mouse model, and is coincident with iron deposits (hemosiderin) known to be deleterious to organ function, possibly due to increased reactive oxygen species . Whole body irradiation has been shown to increase iron content in bone marrow and serum (Zhang et al 2013, Xie et al 2015, and disrupt iron metabolism as well as impair erythropoiesis, which contributes to hemosiderin formation in tissue.…”

The Role of NLRP3 Inflammasome in Radiation-Induced Cardiovascular Injury

“…In addition, local heart radiation resulted in microvascular injury and atherosclerosis in the coronary arteries of Apoe −/− mice that was more extensive (Gabriels et al, 2012). Pathophysiological changes in the cardiovascular systems of small animals exposed to radiation are similar to those in clinical specimens, including increased intima-media thickness and more artery wall lesions (Unthank et al, 2019).…”