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Am J Respir Crit Care Med. 2017 Dec 15;196(12):1571-1581. doi: 10.1164/rccm.201612-2480OC.

Extracellular Mitochondrial DNA Is Generated by Fibroblasts and Predicts Death in Idiopathic Pulmonary Fibrosis.

Author information

1
1 Section of Pulmonary, Critical Care, and Sleep Medicine.
2
2 Yale University School of Bioengineering, New Haven, Connecticut.
3
3 Department of Pharmacology and.
4
4 Department of Pathology, Stony Brook University School of Medicine, Stony Brook, New York.
5
5 Department of Medicine, Medical University of South Carolina, Charleston, South Carolina; and.
6
6 Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
7
7 Section of Endocrinology and Metabolism, and.
8
8 Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut.

Abstract

RATIONALE:

Idiopathic pulmonary fibrosis (IPF) involves the accumulation of α-smooth muscle actin-expressing myofibroblasts arising from interactions with soluble mediators such as transforming growth factor-β1 (TGF-β1) and mechanical influences such as local tissue stiffness. Whereas IPF fibroblasts are enriched for aerobic glycolysis and innate immune receptor activation, innate immune ligands related to mitochondrial injury, such as extracellular mitochondrial DNA (mtDNA), have not been identified in IPF.

OBJECTIVES:

We aimed to define an association between mtDNA and fibroblast responses in IPF.

METHODS:

We evaluated the response of normal human lung fibroblasts (NHLFs) to stimulation with mtDNA and determined whether the glycolytic reprogramming that occurs in response to TGF-β1 stimulation and direct contact with stiff substrates, and spontaneously in IPF fibroblasts, is associated with excessive levels of mtDNA. We measured mtDNA concentrations in bronchoalveolar lavage (BAL) from subjects with and without IPF, as well as in plasma samples from two longitudinal IPF cohorts and demographically matched control subjects.

MEASUREMENTS AND MAIN RESULTS:

Exposure to mtDNA augments α-smooth muscle actin expression in NHLFs. The metabolic changes in NHLFs that are induced by interactions with TGF-β1 or stiff hydrogels are accompanied by the accumulation of extracellular mtDNA. These findings replicate the spontaneous phenotype of IPF fibroblasts. mtDNA concentrations are increased in IPF BAL and plasma, and in the latter compartment, they display robust associations with disease progression and reduced event-free survival.

CONCLUSIONS:

These findings demonstrate a previously unrecognized and highly novel connection between metabolic reprogramming, mtDNA, fibroblast activation, and clinical outcomes that provides new insight into IPF.

KEYWORDS:

biomarkers; interstitial lung disease; mechanotransduction; mitochondria

PMID:
28783377
PMCID:
PMC5754440
[Available on 2018-12-15]
DOI:
10.1164/rccm.201612-2480OC
[Indexed for MEDLINE]

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