Neutrophil Extracellular Traps Regulate the Pathogenesis of Pulmonary Fibrosis by Inducing Epithelial-Mesenchymal Transition

Background Neutrophil extracellular traps released after neutrophil activation are associated with various diseases and redefine the biological functions of neutrophils. Studies have reported a significant increase in the number of neutrophils in the bronchoalveolar lavage fluid and lung tissue of patients with idiopathic pulmonary disease. However,neutrophil-mediated pathogenic mechanisms of idiopathic pulmonary disease remain unclear. Methods The biological functions of neutrophil extracellular traps were evaluated using proliferation,wound healing and transwell assays.The expression of different fibrosis factors was detected using western blot and immunohistochemistry staining in vivo and in vitro. Results Neutrophil extracellular traps promote the proliferation and migration of A549 and BEAS-2B cells by inducing epithelial-mesenchymal transition. Based on our current transcriptome RNA sequencing analysis, ELANE (encoding the neutrophil elastase gene) was a major differentially expressed gene, and the Wnt signaling pathway was the major pathway as demonstrated through Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Neutrophil extracellular traps, through their protease neutrophil elastase interacting with β-catenin, trigger changes in the expression of markers of epithelial-mesenchymal transition, including E-cadherin and vimentin. Additionally, Sivelestat·Na disrupts the stability of neutrophil extracellular traps structures by inhibiting the activity of neutrophil elastase, thereby suppressing neutrophil extracellular traps-induced epithelial-mesenchymal transition, and alleviating acute lung injury and pulmonary fibrosis induced by bleomycin in mice. Conclusions Our results suggest that the neutrophil extracellular traps/Wnt axis promotes the progression of epithelial-mesenchymal transition and the progression of pulmonary fibrosis,recommending it a target for new therapeutic strategies for early-stage pulmonary fibrosis.