Fibroblast growth factor 10 haploinsufficiency causes chronic obstructive pulmonary disease

Abstract

Background Genetic factors influencing lung function may predispose to chronic obstructive pulmonary disease (COPD). The fibroblast growth factor 10 (FGF10) signalling pathway is critical for lung development and lung epithelial renewal. The hypothesis behind this study was that constitutive FGF10 insufficiency may lead to pulmonary disorder. Therefore investigation of the pulmonary functions of patients heterozygous for loss of function mutations in the FGF10 gene was performed. Methods The spirometric measures of lung function from patients and non-carrier siblings were compared and both groups were related to matched reference data for normal human lung function. Results The patients show a significant decrease in lung function parameters when compared to control values. The average FEV1/IVC quota (FEV1%) for the patients is 0.65 (80% of predicted) and reversibility test using Terbutalin resulted in a 3.7% increase in FEV1. Patients with FGF10 haploinsufficiency have lung function parameters indicating COPD. A modest response to Terbutalin confirms an irreversible obstructive lung disease. Conclusion These findings support the idea that genetic variants affecting the FGF10 signalling pathway are important determinants of lung function that may ultimately contribute to COPD. Specifically, the results show that FGF10 haploinsufficiency affects lung function measures providing a model for a dosage sensitive effect of FGF10 in the development of COPD.

Lung epithelial stem cells and their niches: Fgf10 takes center stage

“…In addition, mucus hyperplasia is also frequently observed in lungs from COPD patients [2]. Interestingly, Fgf10 haploinsufficiency is linked to emphysema in COPD in humans, which further emphasizes the significance of Fgf10 expression in adult lung stem cell niches and its role in homeostasis and regeneration [154]. …”

Interactions between NF-κB and SP3 Connect Inflammatory Signaling with Reduced FGF-10 Expression

“…Preterm infants with severe bronchopulmonary dysplasia have reduced saccular airway and alveolar duct formation and have lower FGF-10 expression in their lungs (8,9). In adult patients, Fgf-10 haploinsufficiency can lead to abnormal pulmonary function and chronic obstructive pulmonary disease (10). In both chronic obstructive pulmonary disease and bronchopulmonary dysplasia, lung inflammation plays a key role in disease pathogenesis and also inhibits FGF-10 expression (11)(12)(13).…”

“…Although the expression of multiple receptors provides a diverse detection repertoire at the cell surface, many of these receptors signal through overlapping intracellular pathways that activate the transcription factor NF-B (10,16). In quiescent cells, NF-B resides in the cytoplasm bound to IB.…”

Attenuating endogenous Fgfr2b ligands during bleomycin-induced lung fibrosis does not compromise murine lung repair

“…Administration of Fgf7 or palifermin, a pharmacological agent composed of a truncated form of Fgf7, also reduced fibrosis and increased survival in both rats and mice (7,10,22,32). In humans, haploinsufficiency for FGF10 is associated with chronic obstructive pulmonary disease (COPD) (18). Likewise, in humans, SNPs in FGF7 correlate with increased risk for developing COPD (5).…”