KEY POINTS
- This preclinical study included 37 female C57Bl/6J mice assigned to control irradiation or a single 17.5 Gy whole-thorax dose delivered with FLASH or conventional dose-rate electrons.
- FLASH was delivered at a mean dose rate of 6.1 × 10⁶ Gy/s, compared with 0.238 Gy/s for conventional irradiation. Lung tissue underwent bulk RNA sequencing at 24 hours and 2 weeks.
- At 24 hours, conventional irradiation uniquely upregulated 50 genes and downregulated 27, compared with 6 upregulated and 10 downregulated genes after FLASH. Conventional irradiation enriched ATP-response, leukocyte-adhesion, complement, and chemokine pathways, whereas FLASH did not.
- At 2 weeks, conventional irradiation maintained chemokine activity and increased transcription of macrophage-associated genes including CD68 and CCL9. FLASH reduced expression of CSF2RB and STAT3 relative to conventional irradiation.
- Histology at 3.5 months showed a trend toward less collagen deposition after FLASH, but the difference was not statistically significant.
CLINICAL TAKEAWAY
FLASH produced a less inflammatory and macrophage-associated transcriptional response in healthy mouse lung than conventional dose-rate irradiation, providing a potential mechanistic explanation for normal-tissue sparing. However, this is preliminary preclinical evidence: the experiment used a single high dose, included only female mice, relied on bulk RNA sequencing without protein validation, and did not demonstrate a statistically significant reduction in fibrosis.