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Regulation of Fibrocyte‐derived CXC Chemokine Receptor 4 (CXCR4) by Hypoxia and the Phosphatidylinositol 3‐Kinase (PI‐3‐K)/Mammalian Target of Rapamycin (mTOR) Signaling Pathway
Author(s) -
Oliver Carey J,
Burdick Marie D,
Hong Kurt,
Strieter Robert M
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a179-d
Subject(s) - fibrocyte , myofibroblast , pi3k/akt/mtor pathway , chemokine , cxc chemokine receptors , cancer research , hypoxia (environmental) , pulmonary fibrosis , chemokine receptor , extravasation , lung , microbiology and biotechnology , biology , ly294002 , fibroblast , signal transduction , medicine , fibrosis , pathology , chemistry , immunology , cell culture , inflammation , organic chemistry , oxygen , genetics
The major contributing cell to pulmonary fibrosis is the fibroblast/myofibroblast. Circulating cells with characteristics of a mesenchymal progenitor cell (i.e., fibrocytes) have been found to contribute to pulmonary fibrosis by a mechanism of specific trafficking and extravasation into the lung using CXCR4/CXCL12. On the basis of the importance of this biological axis in the extravasation of fibrocytes into the lung during pathogenesis of pulmonary fibrosis, we hypothesized that targeting expression of CXCR4 on these cells would impact on their ability to traffic to the lung. Recognizing that hypoxia through induction of hypoxia inducible factor‐1 alpha (HIF‐1a) has been shown to regulate the expression of CXCR4 on other cells, we found that fibrocytes isolated from peripheral blood increased their expression of CXCR4 in response to hypoxia. This increased expression correlated with an increase in transcriptional activity of HIF‐1a at the CXCR4 promoter. We further characterized the signaling pathway and found that inhibition of PI‐3‐K by LY294002 reversed hypoxia‐induced CXCR4 expression. Inhibition of mTOR, which is downstream of PI‐3‐K, by rapamycin also blocked increased CXCR4 expression due to hypoxia. We also found increased fibrocyte numbers in the blood and lung of mice exposed to bleomycin, and the inhibition of mTOR by rapamycin attenuated both the circulating number and the magnitude of extravasating fibrocytes into the lung. These studies support the notion that CXCR4/CXCL12 biological axis is important in fibrocyte trafficking to the lung, and pharmacological attenuation of this axis can reduce circulating fibrocytes and impact the magnitude of pulmonary fibrosis.