Background: Pulmonary fibrosis (PF) is a chronic and progressive interstitial lung disease. Histone deacetylases (HDACs) play a crucial role in the onset and development of PF. Changes in HDACs 1–10 expression levels occur during PF development, and their specific roles remain unclear. Therefore, we elucidated changes in the gene and protein levels of HDACs 1–10. Furthermore, we selectively knocked down HDAC2 to explore the molecular mechanism underlying the regulatory role of HDAC2 in epithelialmesenchymal transition (EMT) during the development of PF. Methods: Lewis lung carcinoma (LLC) cells were stimulated with transforming growth factor-β1 (TGF-β1) (5 ng/mL) to establish a lung fibrosis cell model. Additionally, C57BL/6 mice received bleomycin through single intratracheal instillation at a 3.5 mg/kg volume, diluted in 0.7 mL saline. Furthermore, EMT-related gene and protein expression levels were assessed using quantitative PCR (qPCR) and Western blotting, respectively. Results: We observed that HDAC2 expression levels were significantly increased in both the in vitro and in vivo PF models. HDAC2 knockdown significantly decreased the expression levels of fibrosis indicators such as collagen type I (Col-I) and collagen type IV (Col-IV), and EMT indicator α-smooth muscle actin (α-SMA) was observed. Conversely, it increased the expression of EMT indicator E-cadherin (E-cad). Hematoxylin and eosin (H&E) and Masso staining revealed that HDAC2 knockdown substantially reduced the degree of pulmonary fibrosis. These findings suggest that lowering HDAC2 expression inhibits EMT and reduces PF. Moreover, in a TGF-β1-induced lung fibrosis cell model, HDAC2 knockdown significantly reduced epithelial growth factor receptor levels, which inhibited mitogen-activated protein kinases (MAPK) signaling and decreased the protein expression of p38 and c-Jun N-terminal kinase (JNK). Conclusions: HDAC2 knockdown effectively impedes EMT and diminishes PF severity, impacting the JNK/p38 MAPK signaling pathway, which may serve an inhibitory function.

pulmonary fibrosis; HDAC2; epithelial-mesenchymal transition; JNK/p38 MAPK signaling pathways

1.