CXCL14 is a candidate systemic biomarker for hedgehog pathway activity in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) has been associated with the aberrant expression of signaling pathways involved in embryonic development, including the Hedgehog (Hh) pathway. Hh signaling mediates communication between epithelial and mesenchymal cells; Hh ligands are secreted by the epithelium and bind to Patched (PTCH) receptors on mesenchymal cells, releasing the constitutive repression by smoothened (SMO) on the activity of GLI family transcription factors. Hh pathway activity can promote multiple pro-fibrotic processes in mesenchymal cells, including myofibroblast differentiation, expression of extracellular matrix genes, migration, and survival. We observed significantly increased expression levels of Hh pathway genes including SMO, PTCH2, GLI1, and GLI2 in lung tissue from IPF patients as compared to control unused donor lung tissue. To identify candidate systemic biomarkers of Hh pathway activity, we compared genome-wide transcriptional data from IPF lung biopsies and fibroblasts stimulated in vitro with SHh. The gene most significantly upregulated in both datasets was CXCL14, which encodes a soluble secreted chemokine whose expression is inhibited in vitro by the addition of vismodegib, a therapeutic Hh pathway inhibitor. Circulating CXCL14 protein levels were significantly higher in plasma from IPF patients than controls. In solid tumor patients, circulating CXCL14 levels were significantly reduced upon treatment with vismodegib. Taken together, these results suggest that Hh pathway activity is increased in IPF. CXCL14 is a systemic biomarker that could be used to identify IPF patients with increased Hh pathway activity and monitor the pharmacodynamic effects of Hh antagonist therapy in IPF.