LSC - 2024 - Developmental fibroblast growth factor 10 in pathogenesis and reversion of emphysema and PH in COPD

Developmental pathways that orchestrate organ morphogenesis are often disrupted in chronic diseases such as COPD. Emphysema and vascular remodelling in COPD can develop due to aberrant reparative mechanisms. Therefore, our study investigates the role of a critical factor in lung development, fibroblast growth factor 10 (FGF10), in COPD pathogenesis and explores its therapeutic potential. FGF10 expression was examined in primary interstitial lung fibroblasts from COPD and donor lungs. To investigate the relevance of FGF10 in disease development, transgenic mice with impaired FGF10 signalling and a COPD animal model of chronic cigarette smoke (CS) exposure were employed. Therapeutic efficacy was assessed through inducible FGF10 overexpression in transgenic animals or treatment with recombinant FGF10 after established emphysema and PH in mice. COPD fibroblasts exhibited low FGF10 expression due to increased oxidative/nitrosative stress. Mice with impaired FGF10 signalling spontaneously developed emphysema, PH and other pathological features seen in CS-exposed animals. Transcriptomic analysis revealed remarkable similarity between mice with impaired FGF10 signalling and CS-exposed Wt mice. Notably, FGF10 treatment impacted endothelial and alveolar epithelial cells, effectively reversing established experimental emphysema and pulmonary vascular alterations. Impaired FGF10 signalling, due to genetic susceptibility or environmental factors, leads to emphysema and PH development. The FGF10-mediated restoration of lung structures following injury suggests that targeting developmental pathways could serve as a strategy for inducing repair in adult tissues affected by chronic diseases.