Oxymatrine Inhibits Epithelial‐Mesenchymal Transition to Alleviate Airway Remodeling in Chronic Obstructive Pulmonary Disease by Suppressing the <scp>TGF</scp> ‐β1/Smad Pathway

This study explored the therapeutic efficacy of oxymatrine (OMT, C₁₅H₂₄N₂O₂) in a murine model of cigarette smoke (CS)-induced chronic obstructive pulmonary disease (COPD) and elucidated its underlying mechanisms. A COPD model was established in mice through prolonged exposure to CS, followed by intraperitoneal administration of OMT (50 mg/kg) over 3 months. Lung inflammation and fibrosis were evaluated using histopathological techniques (hematoxylin-eosin and Masson staining), enzyme-linked immunosorbent assays (ELISA), and pulmonary function tests. The expression of epithelial-mesenchymal transition (EMT) markers and components of the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway were assessed via Western blot and immunofluorescence. In vitro, human bronchial epithelial (HBE) cells were exposed to CS extract (CSE, 10% v/v) or TGF-β1 (10 ng/mL), with or without treatment using OMT (80 μM) or the TGF-β receptor I inhibitor SB525334 (10 μM). Cell viability, EMT marker expression, and Smad2/3 phosphorylation were measured. In vivo, OMT significantly reduced CS-induced airway inflammation, as evidenced by decreased inflammatory cell infiltration and lower proinflammatory cytokines in bronchoalveolar lavage fluid. OMT treatment improved lung function by restoring compliance, reducing airway resistance, and enhancing forced expiratory capacity. Similarly, OMT alleviated CS-induced pulmonary fibrosis and EMT, as shown by decreased collagen deposition and normalization of EMT marker expression (E-cadherin, vimentin, and α-smooth muscle actin [α-SMA]) in lung tissues. In HBE cells, OMT counteracted EMT induced by CSE or TGF-β1, significantly suppressing Smad2/3 phosphorylation and nuclear translocation. Mechanistic analysis revealed that OMT inhibited activation of the TGF-β1/Smad signaling pathway in both in vivo and in vitro models. Moreover, combining OMT and SB525334 increased EMT suppression in CSE-exposed HBE cells. Importantly, safety evaluations showed no histopathological abnormalities in major organs following OMT administration. In conclusion, these findings indicate that OMT mitigates COPD progression by targeting the TGF-β1/Smad pathway, supporting its potential as a safe and effective therapeutic option for COPD management.