GDF15 is an epithelial-derived biomarker of idiopathic pulmonary fibrosis

Am J Physiol Lung Cell Mol Physiol. 2019 Oct 1;317(4):L510-L521. doi: 10.1152/ajplung.00062.2019. Epub 2019 Aug 21.


Idiopathic pulmonary fibrosis (IPF) is the most common and devastating of the interstitial lung diseases. Epithelial dysfunction is thought to play a prominent role in disease pathology, and we sought to characterize secreted signals that may contribute to disease pathology. Transcriptional profiling of senescent type II alveolar epithelial cells from mice with epithelial-specific telomere dysfunction identified the transforming growth factor-β family member, growth and differentiation factor 15 (Gdf15), as the most significantly upregulated secreted protein. Gdf15 expression is induced in response to telomere dysfunction and bleomycin challenge in mice. Gdf15 mRNA is expressed by lung epithelial cells, and protein can be detected in peripheral blood and bronchoalveolar lavage following bleomycin challenge in mice. In patients with IPF, GDF15 mRNA expression in lung tissue is significantly increased and correlates with pulmonary function. Single-cell RNA sequencing of human lungs identifies epithelial cells as the primary source of GDF15, and circulating concentrations of GDF15 are markedly elevated and correlate with disease severity and survival in multiple independent cohorts. Our findings suggest that GDF15 is an epithelial-derived secreted protein that may be a useful biomarker of epithelial stress and identifies IPF patients with poor outcomes.

Keywords: MIC-1; NAG-1; SASP; aging.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alveolar Epithelial Cells / drug effects
  • Alveolar Epithelial Cells / metabolism*
  • Alveolar Epithelial Cells / pathology
  • Animals
  • Bleomycin / administration & dosage
  • Bronchoalveolar Lavage Fluid / chemistry
  • Case-Control Studies
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Growth Differentiation Factor 15 / genetics*
  • Growth Differentiation Factor 15 / metabolism
  • Humans
  • Idiopathic Pulmonary Fibrosis / diagnosis
  • Idiopathic Pulmonary Fibrosis / genetics*
  • Idiopathic Pulmonary Fibrosis / mortality
  • Idiopathic Pulmonary Fibrosis / physiopathology
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Mice
  • Middle Aged
  • Respiratory Function Tests
  • Severity of Illness Index
  • Survival Analysis
  • Telomere
  • Transcriptome*


  • GDF15 protein, human
  • Gdf15 protein, mouse
  • Growth Differentiation Factor 15
  • Bleomycin