FGF7 gene therapy mitigates airway inflammation and fibrosis in a rat COPD model by restoring epithelial function.

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory airway disease characterized by persistent airflow limitation. A critical factor in its pathogenesis is airway epithelial injury, which disrupts the barrier and impairs repair mechanisms, exacerbating inflammation and fibrosis. Fibroblast growth factor 7 (FGF7), also known as keratinocyte growth factor (KGF), is known to promote alveolar epithelial regeneration after lung injury. However, the precise mechanisms by which FGF7 protects epithelial cells from cigarette smoke (CS)-induced damage in COPD remained largely undefined.

Researchers analyzed FGF7 levels in n=32 human lung tissues (17 COPD, 15 control) and n=71 serum samples (51 COPD, 20 control) using immunohistochemistry, RT-qPCR, Western blot, and ELISA. For in vivo studies, a COPD rat model was established via 12 weeks of CS exposure. These rats received intratracheal administration of AAV-FGF7 or AAV-shFGF7 (a knockdown vector). Lung function was assessed via ventilation parameters, and histology examined inflammation and fibrosis. Cytokine levels in BALF were also measured. In vitro, 16HBE human bronchial epithelial cells were exposed to cigarette smoke extract (CSE) and treated with recombinant FGF7 (with or without inhibitors like SB202190 for p38, LY294002 for PI3K, or AG1478 for EGFR) to evaluate cell viability, migration, and signaling pathway activation.

COPD patients exhibited increased FGF7 levels in lung tissues but decreased serum FGF7 compared to controls. In the CS-exposed rat model, AAV-FGF7 administration significantly improved lung function parameters including MVb/PIFb/EF50, indicating better ventilation. This gene therapy also led to a marked reduction in airway inflammation and peribronchial fibrosis. Furthermore, AAV-FGF7 decreased levels of key inflammatory cytokines and fibrotic mediators in BALF, including IL-1β, IL-6, TNF-α, TGF-β1, and ET-1. Conversely, knockdown of FGF7 via AAV-shFGF7 exacerbated these pathological effects. In the 16HBE cell model, FGF7 treatment restored cell viability and migratory capacity following CSE injury. Mechanistically, FGF7 was found to enhance the phosphorylation of ADAM17 and EGFR, as well as downstream signaling molecules ERK1/2, p38, and AKT. Knockdown of FGF7 inhibited the activation of these pathways, suggesting a crucial role for these signaling cascades in FGF7's protective effects.

AAV-FGF7 gene therapy significantly improved lung function and reduced inflammatory and fibrotic markers in a cigarette smoke-induced COPD rat model, reversing key pathological changes.