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Prevention of radiation-induced bystander effects by agents that inactivate cell-free chromatin released from irradiated dying cells.

ABSTRACT: Radiation-induced bystander effect (RIBE) is a poorly understood phenomenon wherein non-targeted cells exhibit effects of radiation. We have reported that cell-free chromatin (cfCh) particles that are released from dying cells can integrate into genomes of surrounding healthy cells to induce DNA damage and inflammation. This raised the possibility that RIBE might be induced by cfCh released from irradiated dying cells. When conditioned media from BrdU-labeled irradiated cells were passed through filters of pore size 0.22 µm and incubated with unexposed cells, BrdU-labeled cfCh particles could be seen to readily enter their nuclei to activate H2AX, active Caspase-3, NFκB, and IL-6. A direct relationship was observed with respect to activation of RIBE biomarkers and radiation dose in the range of 0.1-0 Gy. We confirmed by FISH and cytogenetic analysis that cfCh had stably integrated into chromosomes of bystander cells and had led to extensive chromosomal instability. The above RIBE effects could be abrogated when conditioned media were pre-treated with agents that inactivate cfCh, namely, anti-histone antibody complexed nanoparticles (CNPs), DNase I and a novel DNA degrading agent Resveratrol-copper (R-Cu). Lower hemi-body irradiation with γ-rays (0.1-50 Gy) led to activation of H2AX, active Caspase-3, NFκB, and IL-6 in brain cells in a dose-dependent manner. Activation of these RIBE biomarkers could be abrogated by concurrent treatment with CNPs, DNase I and R-Cu indicating that activation of RIBE was not due to radiation scatter to the brain. RIBE activation was seen even when mini-beam radiation was delivered to the umbilical region of mice wherein radiation scatter to brain was negligible and could be abrogated by cfCh inactivating agents. These results indicate that cfCh released from radiation-induced dying cells are activators of RIBE and that it can be prevented by treatment with appropriate cfCh inactivating agents.

SUBMITTER: Kirolikar S

PROVIDER: S-EPMC6238009 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Bystanders who drown during a rescue attempt in aquatic waterways are becoming an increasingly important issue within drowning prevention. In the Australian context, the majority of these incidents occur in coastal water ways. This study documents and characterizes bystander rescuer fatalities within Australian coastal waterways that occurred between 1 July 2004 and 30 June 2019 in order to provide suggestions for future public safety interventions involving bystander rescuers. Data was sourced through Surf Life Saving Australia's (SLSA) Coastal Fatality Database, which collates information from multiple sources. Sixty-seven bystander rescuer fatalities in coastal waterways were reported during the 15-year period, an average of 4.5 per year, which is a significant proportion of the five fatalities previously reported across all Australian waterways. The majority of coastal bystander rescuer fatality incidents occurred in the state of New South Wales (49%), at beaches (64%), in regional or remote areas (71%), more than 1 km from the nearest lifesaving service (78%), during summer (45%), in the afternoon (72%), in the presence of rip currents (73%), and did not involve the use of flotation devices to assist rescue (97%). The majority of coastal bystander rescuer victims were Australian residents (88%) born in Australia/Oceania (68%), males (81%), aged between 30-44 years old (36%), visitors to the location (55%), either family (69%) or friends (15%) of the rescuee(s), and were attempting to rescue someone younger than 18 years old (64%). Our results suggest future safety intervention approaches should target males, parents and carers visiting beach locations in regional locations during holiday times and should focus on the importance of flotation devices when enacting a rescue and further educating visitors about the rip current hazard. Future research should examine the psychology of bystander rescue situations and evaluate the effectiveness of different safety intervention approaches.

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Prevention of radiation-induced bystander effects by agents that inactivate cell-free chromatin released from irradiated dying cells.

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