S2578
Radiobiology – Normal tissue radiobiology
ESTRO 2026
Digital Poster Highlight 3578 Dynamic Regulation of Macrophage Polarization by a Synthetic Lipoxin A 4 Analouge in Radiation- induced Lung Injury. CUI RONGLAN, Su-Jin Moon, Jaeho Cho Radiation Oncology, College of Medicine, Yonsei University, Seoul, Korea, Republic of Purpose/Objective: Radiation-induced lung injury (RILI) remains a fatal late complication after thoracic radiotherapy. Macrophages play pivotal roles in both injury progression and tissue repair: classically activated M1 phenotype drives inflammation, whereas alternatively activated M2 phenotype promote resolution but also fibrosis. However, the temporal dynamics of macrophage polarization during the transition from acute inflammation to fibrosis remain unclear. This study aimed to characterize these shifts and to evaluate the therapeutic potential of CYNC-1, a synthetic lipoxin A4 analogue with immuno-
scenarios and strengthen translational research. The kidneys, as radiosensitive late-responding organs, are particularly prone to RT-induced nephropathy (RN). This study retrospectively evaluated chronic renal toxicity following distinct RT regimens in an orthotopic xenograft pancreatic tumor model, adhering to the 3R
principle and emphasizing the importance of prospective normal tissue dose assessment. Material/Methods:
Image-guided RT of pancreatic tumors was performed in an orthotopic xenograft model using MiaPaCa-2 cells and a small animal irradiation system. During the initial treatment planning, renal dose exposure was not specifically constrained. In total, 22 tumor-bearing mice were analyzed: five non-irradiated controls, nine receiving a single-dose RT (25 Gy), and eight treated with a fractionated, biologically equivalent regimen (45.7 Gy in 5 fractions) delivered with a rotational technique. Weekly cone-beam CT (CBCT) imaging was conducted to monitor tumor response. At the end of follow-up, creatinine and blood urea nitrogen (BUN) levels were measured, and kidneys underwent histological evaluation with semiquantitative scoring. Results: Dose distribution analysis revealed close proximity of the left kidney to the high-dose region. CBCT identified left kidney atrophy in 59% of irradiated animals, irrespective of the applied RT regimen. Mean left kidney volume significantly decreased to 58% of baseline during follow-up. Mice developing atrophy had higher mean EQD2 doses to the left kidney compared with those without atrophy. The median time to atrophy was 79 days. Animals exhibiting atrophy showed elevated BUN and creatinine levels compared with both controls and irradiated mice without atrophy. Histological assessment confirmed chronic progressive nephropathy (CPN) characterized by tubular atrophy, proteinaceous deposits, and glomerular as well as interstitial alterations. Right kidneys displayed only mild, subclinical changes. Conclusion: This preclinical RT model closely mirrors clinical conditions and demonstrates chronic renal toxicity following high-dose irradiation. CBCT-detected macroscopic atrophy correlated with histologically confirmed CPN, predominantly in the left kidney adjacent to the high-dose region. These findings highlight the necessity of prospectively applying clinical dose constraints in preclinical studies to mitigate normal tissue toxicity, prevent confounding effects, and enhance translational validity. Keywords: radiation-induced nephropathy, image- guided RT
modulatory activity. Material/Methods:
C57BL/6 mice received a single focal 75Gy irradiation to the left lung using an X-RAD 320 irradiator. Lungs were analyzed at 2, 4, 6 weeks post-irradiation, corresponding to inflammatory, pro-fibrotic and fibrotic phases. Histopathology, flow cytometry, bulk RNA sequencing, western blotting and real-time PCR were performed to assess. In vitro, co-culture of RAW 264.7 macrophages and MLE12 epithelial cells were used to assess macrophage-mediated epithelial responses following CYNC-1 treatment. Results: Markers CD86 (M1 marker) and CD206 (M2 marker) revealed distinct temporal polarization patterns: M2 macrophages predominated during the pro-fibrotic and fibrotic phases, while M1 macrophages persisted across all stages. CYNC-1 administration altered this pattern. Early after irradiation, CYNC-1 enhanced M2 assciated anti-inflammatory activity, reducing acute inflammation. At later stages, it limited excessive M2 accumulation and increased M1/M2 ratio, thereby attenuating collagen deposition and fibrosis. CYNC-1 treated mice exhibited increased expression of lung alveolar epithelial type I cell marker T1 α and preserved alveolar structure. In co-culture, CYNC-1 dynamically modulated macrophage polarization and suppressed epithelial-mesenchymal transition(EMT). Conclusion: CYNC-1 dynamically regulates macrophage polarization in a phase-dependent manner - enhancing early anti-inflammatory repair while restraining late M2-driven fibrosis. This bidirectional modulation effectively mitigated RILI-associated fibrosis in our model. Targeting macrophage re-
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