Is the fibroblast growth factor signaling pathway a victim of receptor tyrosine kinase inhibition in pulmonary parenchymal and vascular remodeling?

摘要

Idiopathic pulmonary arterial hypertension (IPAH), pulmonary hypertension (PH) due to lung disease and/or hypoxia and idiopathic pulmonary flbrosis (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, FGFI0, 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.