Exercise Improves Pulmonary Fibrosis and Neurological Symptoms via S100A12 Inhibition

Yan Sun¹Meng Li¹Jingmin Yuan²Wenrui Li¹Hongli Quan¹Yan Li¹Zhenjing Kang¹Hao Cheng¹Hui Ren¹Mingwei Chen^1*

• ¹The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
• ²Yangtze University, Jingzhou, Hubei Province, China

Background: Neurological symptoms are commonly observed in patients with idiopathic pulmonary fibrosis (IPF). However, the underlying mechanisms remain unclear. Although exercise has been shown to improve pulmonary fibrosis and quality of life in IPF patients, its effects on neurological symptoms in this population are not well understood. Furthermore, a robust animal model linking IPF with comorbid neurological symptoms has not yet been fully developed. Methods: 28 male C57BL/6J mice were divided into four groups: control, bleomycin (BLM), control + exercise, and BLM + exercise. Mice were administered 7.5 mg/kg of BLM or saline, and the exercise groups underwent 45 minutes of treadmill training per day for 28 days. Behavioral tests (OFT, SPT, TST, FST) were performed on days 29-33. Histological analysis assessed pulmonary fibrosis, and biomarkers BDNF and c-Fos were detected. Bioinformatics identified genes altered in IPF, exercise, and depression, validated by Western blotting. Results: BLM induced pulmonary fibrosis and aggravated neurological symptoms.Exercise significantly alleviated these symptoms and reversed the expression of BDNF and c-Fos. Bioinformatics analysis identified 28 genes upregulated in IPF and depression, downregulated by exercise. The S100A12 gene showed reduced expression in both lung and brain tissues in the BLM group and increased expression after exercise. KEGG analysis revealed enrichment in the IL-17 and NOD-like receptor signaling pathways.This study developed a mouse model and suggests that exercise may offer therapeutic benefits for both pulmonary and neurological symptoms in IPF. Shared molecular pathways may guide future therapies targeting both aspects.