期刊
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
卷 60, 期 3, 页码 269-278出版社
AMER THORACIC SOC
DOI: 10.1165/rcmb.2017-0248OC
关键词
lung fibroblast; myofibroblast differentiation; prostaglandin; pulmonary fibrosis; resolution
资金
- National Institutes of Health [R01HL133761, R01HL127001, R01HL120908, T32HL066988, S10RR027926, P30ES001247]
- Guy F. Solimano Fibrosis Research Fund
- Doran Family Endowment
- Wright Family Professorship
- U.S. Army Medical Department
- C. Jane Davis and C. Robert Davis Professorship
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 PGE(2). We report that activation of primary HLFs with IL-1 beta inhibited transforming growth factor beta-induced myofibroblast differentiation in both the IL-1 beta-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 PGE(2). 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.
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