Is the fibroblast growth factor signaling pathway a victim of receptor tyrosine kinase inhibition in pulmonary parenchymal and vascular remodeling?
Elie El AghaFelix SchwindClemens RuppertAndreas GüntherSaverio BellusciRalph T SchermulyDjuro KosanovicPublished in: American journal of physiology. Lung cellular and molecular physiology (2018)
Idiopathic pulmonary arterial hypertension (IPAH), pulmonary hypertension (PH) due to lung disease and/or hypoxia and idiopathic pulmonary fibrosis (IPF) are increasingly recognized as important contributors to mortality and morbidity worldwide. Among others, the current treatment paradigm considers broad inhibition of receptor tyrosine kinases, a strategy that likely leads to collateral inhibition of signaling pathways that are critical for lung repair and regeneration. Fibroblast growth factor 7 (FGF7) and FGF10 signaling in the lung through FGF receptor 2 (FGFR2) are involved in epithelial cell protection and renewal, and mutations in their corresponding genes in humans are linked to increased susceptibility to lung pathologies, such as chronic obstructive pulmonary disease and bronchopulmonary dysplasia. In this report, we present data demonstrating significant upregulation of FGF7, FGF10, and FGFR2 in IPF and IPAH lungs compared with donor lungs. These ligands and their cognate receptor converged on the remodeled parenchyma and vasculature of IPF and IPAH lungs. Interestingly, the expression levels of FGFR1, which has been previously shown to play a pathological role in PH development, were not significantly changed in either disease state. Intriguingly, the expression levels of FGF7, FGF10, and FGFR2 were lower in IPF lung regions undergoing active remodeling, and inversely correlated with IPAH severity, indicating that increased expression might reflect lung repair rather than lung pathology, and warranting further research on the precise role of FGF signaling in pulmonary parenchymal and vascular remodeling.
Keyphrases
- idiopathic pulmonary fibrosis
- pulmonary hypertension
- pulmonary arterial hypertension
- signaling pathway
- poor prognosis
- tyrosine kinase
- chronic obstructive pulmonary disease
- binding protein
- stem cells
- interstitial lung disease
- endothelial cells
- gene expression
- type diabetes
- epithelial mesenchymal transition
- cell proliferation
- epidermal growth factor receptor
- dna methylation
- coronary artery disease
- lung function
- electronic health record
- machine learning