Ligustilide attenuates airway remodeling in COPD mice by covalently binding to MH2 domain of Smad3 in pulmonary epithelium, disrupting the Smad3‐SARA interaction

Abstract

Airway remodeling is one of the hallmarks of chronic obstructive pulmonary disease (COPD) and is closely related to the dysregulation of epithelial‐mesenchymal transition (EMT). Smad3, an important transcriptional regulator responsible for transducing TGF‐β1 signals, is a promising target for EMT modulation. We found that ligustilide (Lig), a novel Smad3 covalent inhibitor, effectively inhibited airway remodeling in cigarette smoke (CS) combined with lipopolysaccharide (LPS)‐induced COPD mice. Oral administration of an alkynyl‐modified Lig probe was used to capture and trace target proteins in mouse lung tissue, revealing Smad3 in airway epithelium as a key target of Lig. Protein mass spectrometry and Smad3 mutation analysis via in‐gel imaging indicated that the epoxidized metabolite of Lig covalently binds to the MH2 domain of Smad3 at Cys331/337. This irreversible bonding destroys the interaction of Smad3‐SARA, prevents Smad3 phosphorylation activation, and subsequently suppresses the nuclear transfer of p‐Smad3, the EMT process, and collagen deposition in TGF‐β1‐stimulated BEAS‐2B cells and COPD mice. These findings provide experimental support that Lig attenuates COPD by repressing airway remodeling which is attributed to its suppression on the activation of EMT process in the airway epithelium via targeting Smad3 and inhibiting the recruitment of the Smad3‐SARA heterodimer in the TGF‐β1/Smad3 pathway.

Magnolol alleviates pulmonary fibrosis inchronic obstructive pulmonary disease by targeting transient receptor potential vanilloid 4‐ankyrin repeat domain

“…Our findings provide a new strategy for the treatment of pulmonary fibrosis and the improvement of respiratory function in COPD patients. As shown in Figure 1a, the model was induced by cigarette smoke (CS) + LPS according to the literature methods with some adjustments (Chen et al, 2016;Cheng et al, 2019;Fang et al, 2019;Lu et al, 2023). Except for the control group, mice in all other groups were exposed to smoking six cigarettes in a plexiglass box for 1 h daily.…”

Research trends on airway remodeling: A bibliometrics analysis

“…The pathological changes include goblet cell metaplasia, extracellular matrix protein deposition and fibrosis, overexpression of angiogenic factors, and proliferation and/or hypertrophy of airway smooth muscle cells [ 2 ]. Airway remodeling is more common in pulmonary diseases such as asthma, COPD, bronchiectasis and cystic fibrosis, which is one of the most challenging problems in these diseases and is also a significant cause of irreversible airway stenosis and airflow limitation [ 3 ]. The crucial role that resident cells play in the pathological progression of airway remodeling is becoming increasingly recognized.…”