Abstract
Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. Elevated levels of hyaluronic acid (HA) have been reported in lungs of patients with IPF. Nintedanib is a kinase inhibitor specific for the receptors of platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF). Its efficacy in patients with IPF has been demonstrated in two phase III clinical trials.
Aim: To determine the in vitro effect of nintedanib on HA-secretion and turnover in human lung fibroblasts.
Methods: Fibroblasts were isolated from lungs derived from patients with IPF. After incubation with nintedanib (0.001 – 1 μM) and stimulation ± PDGF-BB (10 ng/ml), bFGF (10 ng/ml), and VEGF (10 ng/ml), the secretion of HA was measured by enzyme-linked immunosorbent assay, and gene expression of HA metabolizing enzymes (hyaluronic acid synthase [HAS] 1-3, hyaluronidase [HYAL] 1-3) was assessed by quantitative real-time PCR.
Results: PDGF-BB significantly induced HA-secretion and HAS-2 gene expression. bFGF significantly enhanced HA-secretion and reduced HYAL-2 gene expression. Nintedanib significantly i) prevented the PDGF-BB- (p=0.01) and bFGF-induced (p<0.05) secretion of HA, ii) antagonized the PDGF-BB-induced enhanced HAS-2 gene expression (p<0.04), and iii) counteracted the bFGF-induced reduction of HYAL-2 gene expression (p=0.03).
Conclusion: Our data demonstrate that nintedanib prevents PDGF-BB- and bFGF-induced HA-secretion and affects HA turnover. Nintedanib's effect on HA metabolism might be part of the mechanisms underlying the drug's clinically documented beneficial activity.
- Copyright ©ERS 2015