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Am J Respir Cell Mol Biol. 2019 Mar;60(3):269-278. doi: 10.1165/rcmb.2017-0248OC.

Activated Human Lung Fibroblasts Produce Extracellular Vesicles with Antifibrotic Prostaglandins.

Author information

1
1 Department of Environmental Medicine.
2
2 Lung Biology and Disease Program, and.
3
3 Division of Pulmonary Diseases and Critical Care, and.
4
4 Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York.

Abstract

The differentiation of interstitial lung fibroblasts into contractile myofibroblasts that proliferate and secrete excessive extracellular matrix is critical for the pathogenesis of pulmonary fibrosis. Certain lipid signaling molecules, such as prostaglandins (PGs), can inhibit myofibroblast differentiation. However, the sources and delivery mechanisms of endogenous PGs are undefined. Activated primary human lung fibroblasts (HLFs) produce PGs such as PGE2. We report that activation of primary HLFs with IL-1β inhibited transforming growth factor β-induced myofibroblast differentiation in both the IL-1β-treated cells themselves (autocrine signal) and adjacent naive HLFs in cocultures (paracrine signal). Additionally, we demonstrate for the first time that at least some of the antifibrotic effect of activated fibroblasts on nearby naive fibroblasts is carried by exosomes and other extracellular vesicles that contain several PGs, including high levels of the antifibrotic PGE2. Thus, activated fibroblasts communicate with surrounding cells to limit myofibroblast differentiation and maintain homeostasis. This work opens the way for future research into extracellular vesicle-mediated intercellular signaling in the lung and may inform the development of novel therapies for fibrotic lung diseases.

KEYWORDS:

lung fibroblast; myofibroblast differentiation; prostaglandin; pulmonary fibrosis; resolution

Comment in

PMID:
30265126
PMCID:
PMC6397975
[Available on 2020-03-01]
DOI:
10.1165/rcmb.2017-0248OC

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