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.