GDF15 is an epithelial-derived biomarker of idiopathic pulmonary fibrosis.

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

doi:10.1152/ajplung.00062.2019

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.

Highlights

Idiopathic pulmonary fibrosis (IPF) is the most common and devastating of the idiopathic interstitial pneumonias [47]
The top transcript from this analysis mapped to Gdf15, and we confirmed its differential expression by quantitative PCR in purified AEC2s (Fig. 1, A and B)
GDF15 was strongly expressed by airway cells by RNA in situ hybridization (RNAISH) and could be identified in AEC2s following induction of telomere dysfunction in Trf2Fl/FlSftpc-CreER mice (Fig. 1, C and D, and Supplemental Fig. S1A)

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is the most common and devastating of the idiopathic interstitial pneumonias [47]. The full etiology of IPF is not fully understood; strides have been made in recent years, largely driven by genetic association and familial studies that have focused interest on epithelial dysfunction as a primary driver of disease [12, 41]. SFTPC, SFTPA1, and SFTPA2, cause type II alveolar epithelial cell (AEC2)-specific injury and are responsible for 1–3% of familial pulmonary fibrosis cases [41]. Mutations in genes related to telomere biology, responsible for ~30% of familial [7, 8, 13, 18, 50] and ~10% of sporadic cases [23, 46], likely limit the proliferative capacity of the epithelium and increase epithelial senescence [3, 12]. While the function of all SASP-associated proteins is not known, several components are thought to promote inflammation and wound healing [19, 21]

Methods

Results

Conclusion