LAMC2 Drives Airway Remodeling in COPD via EMT Regulation Through the AKT Pathway

Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow limitation, largely driven by airway remodeling. Epithelial-mesenchymal transition (EMT) is a key mechanism underlying this process. Laminin subunit gamma-2 (LAMC2) is implicated in fibrosis and EMT, but its role in COPD-associated airway remodeling remains unclear.

Differential expression analysis was performed using airway epithelial cell datasets from COPD patients and TGF-β1-induced EMT models. Findings were validated in COPD patient lung tissues, smoke-exposed mice, and in vitro experiments. In vivo, chronic smoke-exposed mice were pre-treated intratracheally with adeno-associated virus (AAV)-shLAMC2. Functional assays involved siRNA knockdown or plasmid overexpression of LAMC2 in bronchial epithelial cells. RNA sequencing and pathway analyses were conducted to explore underlying mechanisms.

LAMC2 was significantly upregulated in COPD patient and murine airway epithelia. AAV-shLAMC2 administration alleviated airway remodeling and restored epithelial E-cadherin while reducing mesenchymal markers (N-cadherin, fibronectin), indicating attenuation of EMT. In vitro, LAMC2 was upregulated in TGF-β1-stimulated epithelial cells, and its modulation significantly influenced EMT progression. Transcriptomic analysis suggested that AKT signaling as a potential downstream of LAMC2, supported by functional assays.

LAMC2 is upregulated in COPD airway epithelium and promotes airway remodeling by regulating EMT, potentially through AKT signaling. These findings suggest that targeting LAMC2 may represent a potential strategy for mitigating COPD-associated airway remodeling.