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

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

Am J Respir Crit Care Med. 2017 Aug 07;:

Authors: Ryu C, Sun H, Gulati M, Herazo-Maya JD, Chen Y, Osafo-Addo A, Brandsdorfer C, Winkler J, Blaul C, Faunce J, Pan H, Woolard T, Tzouvelekis A, Antin-Ozerkis DE, Puchalski JT, Slade M, Gonzalez AL, Bogenhagen DF, Kirillov V, Feghali-Bostwick C, Gibson K, Lindell K, Herzog RI, Dela Cruz CS, Mehal W, Kaminski N, Herzog E, Trujillo G

Abstract
RATIONALE: Idiopathic pulmonary fibrosis (IPF) involves the accumulation of alpha smooth muscle actin (αSMA) expressing myofibroblasts arising from interactions with soluble mediators such as transforming growth factor beta-1 (TGFβ1), and mechanical influences such as local tissue stiffness. While 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 TGFβ1 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, and in plasma samples from two longitudinal IPF cohorts and demographically-matched controls. Measurements and Main Results Exposure to mtDNA augments αSMA expression in NHLFs. The metabolic changes in NHLFs that are induced by interactions with TGFβ1 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.

PMID: 28783377 [PubMed - as supplied by publisher]

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