Radioprotective effect of X‐ray abdominal FLASH irradiation: Adaptation to oxidative damage and inflammatory response may be benefiting factors

Abstract

Background Ultrahigh dose‐rate irradiation (FLASH‐IR) was reported to be efficient in tumor control while reducing normal tissue radiotoxicity. However, the mechanism of such phenomenon is still unclear. Besides, the FLASH experiments using high energy X‐ray, the most common modality in clinical radiotherapy, are rarely reported. This study aims to investigate the radiobiological response using 6 MV X‐ray FLASH‐IR or conventional dose‐rate IR (CONV‐IR). Methods The superconducting linac of Chengdu THz Free Electron Laser (CTFEL) facility was used for FLASH‐IR, a diamond radiation detector and a CeBr3 scintillation detector were used to monitor the time structure and dose rate of FLASH pulses. BALB/c nude mice received whole abdominal 6 MV X‐ray FLASH‐IR or CONV‐IR, the prescribed dose was 15 Gy or 10 Gy and the delivered absolute dose was monitored with EBT3 films. The mice were either euthanized 24 h post‐IR to evaluate acute tissue responses or followed up for 6 weeks to observe late‐stage responses and survival probability. Complete blood count, histological analyses, and measurement of cytokine expression and redox status were performed. Results The mean dose rate of >150 Gy/s and instantaneous dose rate of >5.5 × 105 Gy/s was reached in FLASH‐IR at the center of mice body. After 6 weeks’ follow‐up of mice that received 15 Gy IR, the FLASH group showed faster body weight recovery and higher survival probability than the CONV group. Histological analysis showed that FLASH‐IR induced less acute intestinal damage than CONV‐IR. Complete blood count and cytokine concentration measurement found that the inflammatory blood cell counts and pro‐inflammatory cytokine concentrations were elevated at the acute stage after both FLASH‐IR and CONV‐IR. However, FLASH irradiated mice had significantly fewer inflammatory blood cells and diminished pro‐inflammatory cytokine at the late stage. Moreover, higher reactive oxygen species (ROS) signal intensities but significantly reduced lipid peroxidation were found in the FLASH group than in the CONV group in the acute stage. Conclusions The radioprotective effect of 6 MV X‐ray FLASH‐IR was observed. The differences in inflammatory responses and redox status between the two groups may be the factors responsible for reduced radiotoxicities following FLASH‐IR. Further studies are required to thoroughly evaluate the impact of ROS on FLASH effect.

Comparison of intratumor and local immune response between MV X-ray FLASH and conventional radiotherapies

“…FLASH-RT was performed using the Chengdu THz Free Electron Laser (CTFEL) facility that produces 6 MV bremsstrahlung X-rays [4] , [5] . A 5-cm-thick lead shield with a 2-cm (craniocaudal) × 4-cm (lateral) window was used for FLASH-RT, and the mice received RT at a source surface distance (SSD) of 13.5 cm.…”

“…For example, a series of preclinical studies have shown that FLASH-RT reduced the expression levels of transforming growth factor-beta, a maker of tissue damage and a key switch for fibrosis initiation [20] , [21] . A previous study found that FLASH-irradiated BALB/c nude mice had significantly fewer inflammatory blood cells and diminished pro-inflammatory cytokines 4 weeks post-irradiation (PI), which might be beneficial factors in reducing radiotoxicity after FLASH-RT [4] .…”

“…Ultra-high dose rate radiotherapy (FLASH-RT) has received considerable attention as a series of studies have shown that FLASH-RT can spare normal tissues from radiation toxicity while retaining tumor repression capabilities [1] , [2] , [3] , [4] , [5] . Such phenomenon is referred to as the “FLASH effect” and has been proven in different preclinical models, including mouse [1] , [2] , [6] , [7] , [8] , zebrafish embryos [9] , [10] , canine [11] , mini pigs, and cat [12] models.…”

Mechanisms of FLASH effect

“…The results showed that FLASH-RT had less expression of pro-inflammatory factor gene (EGR1) and lower up-regulation of inflammatory factor (TGF-b1, NF-KB) than COVN-RT. Zhu et al (26) reported the changes of immune and inflammatory responses after FLASH-RT(>150Gy/s, 10Gy and 15Gy) irradiation on the intestine of mice(BALB/c). X-ray was used in Zhu's study.…”

Potential Molecular Mechanisms behind the Ultra-High Dose Rate “FLASH” Effect

“…An average dose rate above 40 Gy/s has long been the main characteristic that defines FLASH RT. However, it seems that a higher dose rate is often needed to observe a reduction in normal tissue toxicity, depending on the target tissue (brain [ 24 , 32 , 34 ] and abdomen [ 25 , 42 , 44 ] vs. thorax [ 17 , 36 , 37 , 38 ]) and the used in vivo model (zebrafish embryos [ 22 ] vs. mice [ 31 , 46 ]). In addition to the dose rate, a dose threshold also strongly impacts the FLASH effect.…”