Delayed Effects of Acute Radiation Exposure in a Murine Model of the H-ARS

Abstract

The threat of radiation exposure from warfare or radiation accidents raises the need for appropriate animal models to study the acute and chronic effects of high dose rate radiation exposure. The goal of this study was to assess the late development of fibrosis in multiple organs (kidney, heart, and lung) in survivors of the C57BL/6 mouse model of the hematopoietic-acute radiation syndrome (H-ARS). Separate groups of mice for histological and functional studies were exposed to a single uniform total body dose between 8.53 and 8.72 Gy of gamma radiation from a 137Cs radiation source and studied 1–21 months later. Blood urea nitrogen levels were elevated significantly in the irradiated mice at 9 and 21 mo (from ~22 to 34 ± 3.8 and 69±6.0 mg/dl, p<0.01 vs non-irradiated controls) and correlated with glomerosclerosis (29±1.8% vs 64±9.7% of total glomeruli, p<0.01 vs non-irradiated controls). Glomerular tubularization and hypertrophy and tubular atrophy were also observed at 21 mo post-total body irradiation (TBI). An increase in interstitial, perivascular, pericardial and peri-bronchial fibrosis/collagen deposition was observed from ~9–21 mo post-TBI in kidney, heart and lung of irradiated mice relative to age-matched controls. Echocardiography suggested decreased ventricular volumes with a compensatory increase in left ventricular ejection fraction. The results indicate that significant delayed effects of acute radiation exposure occur in kidney, heart, and lung in survivors of the murine H-ARS TBI model which mirrors pathology detected in larger species and humans at higher radiation doses focused on specific organs.

Late Effects of Total-Body Gamma Irradiation on Cardiac Structure and Function in Male Rhesus Macaques

“…This modest difference between studies may be in part due to the inclusion of females and postirradiation treatment with bone marrow transplants ( 39 ), which were not used in our study ( 41 – 43 ). Similar observations were recently reported in a murine model of radiation exposure, where LVDs was significantly lower ( P < 0.05) and LVDd tended to be lower ( P = 0.06) ( 44 ). The smaller LV dimension measurements are consistent with a restrictive cardiomyopathy due to fibrosis, although reduced relaxation or blunted growth of the heart postirradiation could play a role.…”

“…In the murine model noted above, fractional shortening also tended to be increased ( P = 0.10) ( 44 ). The mechanisms underlying the tendency towards increased fractional shortening are unclear, but may represent a compensatory response to promote adequate cardiac output and blood flow.…”

Delayed effects of acute whole body lethal radiation exposure in mice pre-treated with BBT-059

“…Survivors of ARS, both those administered a countermeasure and those who are not, may experience delayed effects of acute radiation exposure (DEARE), DEARE can manifest chronic illnesses that affect multiple organ systems 10 . There is a need to better understand the underlying mechanisms that result in long-term syndromes that occur in multiple organs, as well to identify novel therapies that both improve the initial insult of TBI as well as the lasting DEARE.…”

“…DEARE was studied in an early publication by Lawrence and Tennant 11 and since that time a number of studies to further our understanding have been published 10,[12][13][14][15][16][17][18][19][20] . Several of these studies have addressed DEARE in irradiated animals without the use of radiation countermeasures at set time points relative to TBI.…”

“…Several of these studies have addressed DEARE in irradiated animals without the use of radiation countermeasures at set time points relative to TBI. These studies can offer valuable insights into changes that occur as a result of exposure to ionizing radiation including fibrosis in major organs 10 and significant loss of long term repopulating potential in bone marrow 17 .…”