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Mechanism of silica nanoparticles induced pulmonary epithelial-mesenchymal transition mediated by exosomal HNRNPAB
Xiaoxu Zhao1, Yujie Pan1, Guanghao Yan1
1Department of Occupational Medicine and Clinical Toxicology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
Background:
Despite the widespread application of silica nanoparticles (SiNPs) and their known risk of pulmonary toxicity, their effects on lymphatic endothelial cells (LECs) and the mechanisms by which they promote pulmonary epithelial-mesenchymal transition (EMT) and fibrosis are poorly understood. This study aimed to elucidate the role of LEC-derived exosomes (LEC-Exos) and a key exosomal protein, heterogeneous nuclear ribonucleoprotein A/B (HNRNPAB), in SiNP-induced pulmonary EMT.
Methods:
Human LECs and A549 cells were treated with SiNPs. Exosomes were isolated from LECs and characterized using nanoparticle tracking analysis, transmission electron microscopy, and western blotting. Proteomic analysis was used to identify the differentially expressed exosomal proteins. EMT was evaluated by assessing cell morphology and the expression of related markers (E-cadherin, N-cadherin, and Snail). The functional role of HNRNPAB in LECs was confirmed using knockdown experiments. An in vivo rat model of pulmonary EMT using Wistar rats was established using intratracheal instillation of SiNPs, and lung tissues were examined for fibrotic changes, lymphangiogenesis, and HNRNPAB expression.
Results:
SiNPs altered the proteome composition of LEC-Exos and upregulated HNRNPAB expression. Exosomes from SiNP-treated LECs (Si-LEC-Exos) induced EMT in A549 cells at lower concentrations than the control exosomes, and synergistic effects were observed when they were combined with SiNPs. HNRNPAB knockdown significantly reduces EMT induction. In rats, SiNP exposure causes pulmonary fibrosis, lymphatic hyperplasia, and elevated HNRNPAB expression, particularly in the peribronchial regions. Mechanistically, Si-LEC-Exos activated the AKT/ERK pathway and increased HNRNPAB expression, thereby enhancing Snail-mediated EMT.
Conclusion:
SiNPs can significantly promote pulmonary epithelial-mesenchymal transition through an LEC-Exos-dependent pathway, in which HNRNPAB plays a critical regulatory role. These findings provide novel insights into the pathogenesis of SiNP-induced pulmonary fibrosis and highlight the potential of LEC-Exos and HNRNPAB as therapeutic targets.
