Radioactive Iodine-131 aerosols induce rat pulmonary fibrosis via miR-34c-5p/ARHGAP1 axis-mediated fibroblast activation.

Abstract

Following nuclear accidents, Iodine-131 (131I) released as radioactive aerosols can be inhaled into the lungs, leading to radiation-induced pulmonary fibrosis (RIPF). Our previous studies have identified miR-34c-5p as a potential biomarker for 131I internal exposure, which is significantly downregulated upon 131I irradiation and is known to negatively regulate fibrogenic processes. However, it remains unclear whether inhaled 131I aerosols induce RIPF by downregulating miR-34c-5p in fibroblasts and consequently activating these effector cells. Here, 131I-labeled silk fibroin microparticles (SFMPs) were used to simulate radioactive aerosols, and intratracheal instillation was performed to mimic the inhalation of 131I-aerosols in rats. The results indicate that 131I-aerosols deposition induced RIPF in rats, accompanied by miR-34c-5p downregulation, and exogenous administration of miR-34c-5p alleviated fibrosis. Mechanistically, miR-34c-5p was downregulated in 131I-induced fibroblast activation, and Rho GTPase-activating protein 1 (ARHGAP1) was verified as its direct target; ARHGAP1 overexpression reversed the inhibitory effect of miR-34c-5p on 131I-induced fibroblast activation. Notably, in a thyroid cancer patient with lung metastasis, serum miR-34c-5p levels decreased following 131I accumulation in lung metastases. These findings demonstrate that 131I aerosols induce rat RIPF via the miR-34c-5p/ARHGAP1 axis-mediated fibroblast activation, providing a potential therapeutic target for internal radiation-related pulmonary fibrosis.