FGF7 mitigates airway inflammation and epithelial injury in cigarette smoke-induced COPD model

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory airway disease marked by persistent airway limitation. Airway epithelial injury is pivotal in the onset and progression of COPD. Fibroblast growth factor 7 (FGF7) has been reported to promote alveolar epithelial regeneration following lung injury. Nonetheless, how FGF7 protects epithelial cells against cigarette smoke (CS)-induced airway injury remained unclear.

FGF7 levels were analyzed in human lung tissues (n=32; 17 COPD and 15 control subjects) and serum samples (n=71; 51 COPD and 20 control subjects) using immunohistochemistry, RT-qPCR, Western blot, and ELISA. In a COPD rat model subjected to CS exposure for 12 weeks, the impact of intratracheal administration of AAV-FGF7 or AAV-shFGF7 on lung function was assessed by lung ventilation and histology, expression levels of cytokines, and other signaling molecules. In the CSE-injured 16HBE cell model, recombinant FGF7 was applied with or without SB202190 (a p38 inhibitor), LY294002 (a PI3K inhibitor), or AG1478 (an EGFR inhibitor) to evaluate cell viability, migratory capacity, cytokine production, and activation of corresponding signaling pathways.

COPD patients demonstrated an increased level of FGF7 in lung tissues, while serum FGF7 levels decreased. In the rat model, CS exposure led to heightened airway inflammation, collagen deposition, and elevated cytokine levels in bronchoalveolar lavage fluid (BALF). Transfection of AAV-FGF7 resulted in improvements in MVb/PIFb/EF50, a reduction in inflammation and peribronchial fibrosis, and decreased levels of IL-1β, IL-6, TNF-α, TGF-β1, and ET-1 in BALF. Correspondingly, AAV-shFGF7 aggravated these pathological effects. FGF7 was found to enhance the phosphorylation of ADAM17 and EGFR, as well as ERK1/2, p38, and AKT, whereas knockdown of FGF7 inhibited the activation of these signaling pathways. In 16HBE cells, FGF7 was observed to restore cell viability and migration, suppress cytokine release, and activate ADAM17, EGFR, and ERK1/2, and these effects were diminished by the blockade of p38, PI3K, or EGFR.

FGF7 is specifically upregulated in the lung tissues of COPD patients. It mitigates CS-induced airway epithelial damage and inflammation through the ADAM17-dependent EGFR-ERK1/2 axis, p38, and PI3K/AKT pathways. FGF7 therefore emerges as a promising therapeutic target for interventions aimed at preventing airway remodeling in COPD.