Differential metabolism of hyaluronic acid in patients with idiopathic pulmonary fibrosis

Abstract

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. Hyaluronic acid (HA) is the most abundant glycosaminoglycan of the extracellular matrix and its accumulation has been demonstrated in lungs of patients with IPF. Both basic fibroblast growth factor (bFGF) and platelet-derived growth factor-BB (PDGF-BB) influence HA secretion and metabolism. Aim: To study the effect of bFGF and PDGF-BB on HA secretion and metabolism in primary human lung fibroblasts derived from IPF patients as compared to control cells. Methods: Fibroblasts were isolated from lungs derived from IPF patients and from healthy control subjects. After stimulation with PDGF-BB (10 ng/ml) or bFGF (10 ng/ml) HA-secretion was measured by ELISA 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: bFGF and PDGF-BB significantly enhanced HA-secretion in IPF as well as control cells. In control but not in IPF fibroblasts, HAS-2 gene expression was 5-fold increased by bFGF (p=0.002). bFGF and PDGF-BB suppressed HAS-3 gene expression in control cells by 78% for PDGF-BB, and by 65% for bFGF, while in IPF cells the suppression was 33% for PDGF-BB, and 43% for bFGF. HYAL-1 gene expression was significantly induced by PDGF-BB in IPF cells by 46% (p=0.02), but suppressed in control cells by 58% (p=0.0007). Conclusion: Our data demonstrate IPF-specific differences for the gene expression of two HA-metabolizing enzymes. Altered HA metabolism might therefore constitute a pivotal part in the pathogenesis of IPF.