High-dose vitamin C attenuates radiation-induced pulmonary fibrosis by targeting S100A8 and S100A9

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2024-10, Vol.1870 (7), p.167358, Article 167358
• Main Authors: Ma, Li, Jin, Yu, Aili, Aifeina, Xu, Liang, Wang, Xi, Xiao, Lingyan, Zhao, Weiheng, Yin, Shiyu, Liu, Bo, Yuan, Xianglin
• Format: Article
• Language: English
• Subjects: Animals; Ascorbic Acid - administration & dosage; Ascorbic Acid - pharmacology; Ascorbic Acid - therapeutic use; Calgranulin A - genetics; Calgranulin A - metabolism; Calgranulin B - genetics; Calgranulin B - metabolism; Disease Models, Animal; High-dose vitamin C; Humans; Male; Mice; Mice, Inbred C57BL; Neutrophils; Pulmonary Fibrosis - drug therapy; Pulmonary Fibrosis - etiology; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Pulmonary Fibrosis - prevention & control; Radiation-induced pulmonary fibrosis; S100A8; S100A9
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167358

Radiation-induced pulmonary fibrosis (RIPF) is a frequently encountered late complication in patients undergoing radiation therapy, presenting a substantial risk to patient mortality and quality of life. The pathogenesis of RIPF remains unclear, and current treatment options are limited in efficacy. High-dose vitamin C has demonstrated potential when used in conjunction with other adjuvant therapies due to potent anticancer properties. However, the potential relationship between high-dose vitamin C and RIPF has not yet been explored in existing literature. In our study, the RIPF model and the LLC tumor model were used as two animal models to explore how high-dose vitamin C can improve RIPF without hampering the antitumour efficacy of radiotherapy. The impact of high-dose vitamin C on RIPF was assessed through various assays, including micro-CT, HE staining, Masson staining, and immunohistochemistry. Our results indicated that administering high-dose vitamin C 2 days before radiation and continuing for a duration of 6 weeks significantly inhibited the progression of RIPF. In order to explore the mechanism by which high-dose vitamin C attenuates RIPF, we utilized RNA-seq analysis of mouse lung tissue in conjunction with publicly available databases. Our findings indicated that high-dose vitamin C inhibits the differentiation of fibroblasts into myofibroblasts by targeting S100A8 and S100A9 derived from neutrophils. Additionally, the combination of high-dose vitamin C and radiation demonstrated enhanced inhibition of tumor growth in a murine LLC tumor model. These results revealed that the combination of radiotherapy and high-dose vitamin C may offer a promising therapeutic approach for the clinical management of thoracic tumors and the prevention of RIPF. •High-dose vitamin C attenuated RIPF in a schedule-dependent manner.•High-dose vitamin C alleviated RIPF by targeting S100A8/9 derived from neutrophils.•High-dose vitamin C combined with radiation exhibited a notable antitumor effect.