Related Experiment Video
Updated: Oct 26, 2026
Establishment and Validation of a Rat Model of Pulmonary Arterial Hypertension Associated with Pulmonary Fibrosis
Published on: May 23, 2025
Photon FLASH spares radiation-induced lung injury and pulmonary hypertension in a preclinical model
Kathryn H Brown1, Mihaela Ghita-Pettigrew1, Louis McCabe1
1Johnston Cancer Research Centre, Queen's University Belfast, Northern Ireland, UK.
Introduction:
Ultra-high dose rate (UHDR) radiotherapy has shown significant promise in reducing normal tissue toxicities with equivalent tumour control compared to conventional (CONV) dose rates termed the FLASH effect. In this study, we compared radiation-induced lung injury and changes in the pulmonary circulation following localised right lung irradiation at UHDR and CONV exposures using photons.
Methods:
Acute and late pulmonary radiation responses were assessed in pneumonitis (C3H/NeJ) and fibrosis prone (C57BL/6) mice. 18 Gy was delivered to the right lung at CONV (0.05 Gy/s), FLASH (76.2 Gy/s) and FLASH split dose (FSD, average 2.6 Gy/s) exposures. Early responses (72 h and 4 weeks after irradiation) were investigated by immunohistochemistry (Ly6G, F4/80), fluorescence staining (EdU) and serum profiling (cytokines and lipid peroxidation assays). Fibrosis was assessed at 30 weeks after irradiation by cone-beam CT (CBCT) analysis and quantification of collagen, senescence (p21) and TGF-β levels. Changes in pulmonary vasculature and transthoracic echocardiography (TTE) was assessed in C57BL/6 mice at 30 weeks to characterise changes in pulmonary circulation associated with pulmonary hypertension (PH).
Results:
At early timepoints, UHDR exposures led to reduced immune cell infiltration (neutrophils and macrophages) and tissue damage in comparison to CONV and FSD groups. Serum analysis supported FLASH sparing with decreased levels of markers associated with chronic inflammation and increased markers of tissue repair in comparison to CONV and FSD groups. At 30 weeks after irradiation at a UHDR, the lung parenchyma was structurally similar to controls (p = 0.33) with minimal collagen deposition supported by CBCT tissue density analysis. In contrast, CONV and FSD animals showed significant collagen deposition (p < 0.01) with thickened alveolar septa and reduced alveolar air spaces. UHDR exposures significantly reduced functional and histological metrics of PH (p < 0.05) compared to CONV.
Conclusions:
UHDR photons significantly reduce radiation-induced pneumonitis and fibrosis with secondary effects on the pulmonary circulation sparing PH.
