CSF3 aggravates acute exacerbation of pulmonary fibrosis by disrupting alveolar epithelial barrier integrity

作者：Bingnan Guo, Wenwen Liu, Xuan Ji, Bin Xi, Xiao Meng, Wanwan Xie, Yitian Sun, Maowei Zhang, Pingli Liu, Wenhui Zhang, Xianliang Yan, Bi Chen · 发表于：International Immunopharmacology · 年份：2024 · DOI：10.1016/j.intimp.2024.112322 · 被引用次数：2 · 研究领域：Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Neonatal Respiratory Health Research、Pleural and Pulmonary Diseases

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive respiratory disorder characterized by poor prognosis, often presenting with acute exacerbation. The primary cause of death associated with IPF is acute exacerbation of IPF (AE-IPF). However, the pathophysiology of acute exacerbation has not been clearly elucidated yet. This study aims to investigate the underlying pathophysiological molecular mechanism in a mouse AE-PF model. C57BL/6J mice were intratracheally administered bleomycin (BLM, 5 mg/kg) to induce pulmonary fibrosis. After 14 days, lipopolysaccharide (LPS, 2 mg/kg) was injected via the trachea route. Histological assessments, including H&E and Masson staining, as well as inflammatory indicators, were included to evaluate the induction of AE-PF by BLM and LPS in mice. Transcriptomic profiling of pulmonary tissues identified CSF3 as one of the top 10 upregulated DEGs in AE-PF mice. Indeed, administration of exogenous CSF3 protein exacerbated AE-PF in mice. Mechanistically, CSF3 disrupted alveolar epithelial barrier integrity and permeability by regulating specialized cell adhesion complexes such as tight junctions (TJs) and adherens junctions (AJs) via PI3K/p-Akt/Snail pathway, contributing to the aggravation of AE-PF in mice. Moreover, the discovery of elevated sera CSF3 indicated a notable increase in IPF patients during the exacerbation of the disease. Pearson correlation analysis in IPF patients revealed significant positive associations between CSF3...