GDF15 is an epithelial-derived biomarker of idiopathic pulmonary fibrosis

Yingze Zhang, Mao Jiang, Mehdi Nouraie, Mark G. Roth, Tracy Tabib, Spencer Winters, Xiaoping Chen, John Sembrat, Yanxia Chu, Nayra Cardenes, Rubin M. Tuder, Erica L. Herzog, Changwan Ryu, Mauricio Rojas, Robert Lafyatis, Kevin F. Gibson, John F. McDyer, Daniel J. Kass, Jonathan K. Alder

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)L510-L521
JournalAmerican journal of physiology. Lung cellular and molecular physiology
Volume317
Issue number4
DOIs
StatePublished - Oct 1 2019

Keywords

  • MIC-1
  • NAG-1
  • SASP
  • aging

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Fingerprint Dive into the research topics of 'GDF15 is an epithelial-derived biomarker of idiopathic pulmonary fibrosis'. Together they form a unique fingerprint.

  • Cite this

    Zhang, Y., Jiang, M., Nouraie, M., Roth, M. G., Tabib, T., Winters, S., Chen, X., Sembrat, J., Chu, Y., Cardenes, N., Tuder, R. M., Herzog, E. L., Ryu, C., Rojas, M., Lafyatis, R., Gibson, K. F., McDyer, J. F., Kass, D. J., & Alder, J. K. (2019). GDF15 is an epithelial-derived biomarker of idiopathic pulmonary fibrosis. American journal of physiology. Lung cellular and molecular physiology, 317(4), L510-L521. https://doi.org/10.1152/ajplung.00062.2019