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    TRIP-1 via AKT modulation drives lung fibroblast/myofibroblast trans-differentiation

    Nyp, Michael F
    Navarro, Angels
    Rezaiekhaligh, Mohammad H
    Perez, Ricardo E
    Mabry, Sherry M
    Ekekezie, Ikechukwu I
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    Date
    2014-02-15
    Format
    Journal Article
    Metadata
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    Abstract
    Abstract Background Myofibroblasts are the critical effector cells in the pathogenesis of pulmonary fibrosis which carries a high degree of morbidity and mortality. We have previously identified Type II TGFβ receptor interacting protein 1 (TRIP-1), through proteomic analysis, as a key regulator of collagen contraction in primary human lung fibroblasts—a functional characteristic of myofibroblasts, and the last, but critical step in the process of fibrosis. However, whether or not TRIP-1 modulates fibroblast trans-differentiation to myofibroblasts is not known. Methods TRIP-1 expression was altered in primary human lung fibroblasts by siRNA and plasmid transfection. Transfected fibroblasts were then analyzed for myofibroblast features and function such as α-SMA expression, collagen contraction ability, and resistance to apoptosis. Results The down-regulation of TRIP-1 expression in primary human lung fibroblasts induces α-SMA expression and enhances resistance to apoptosis and collagen contraction ability. In contrast, TRIP-1 over-expression inhibits α-SMA expression. Remarkably, the effects of the loss of TRIP-1 are not abrogated by blockage of TGFβ ligand activation of the Smad3 pathway or by Smad3 knockdown. Rather, a TRIP-1 mediated enhancement of AKT phosphorylation is the implicated pathway. In TRIP-1 knockdown fibroblasts, AKT inhibition prevents α-SMA induction, and transfection with a constitutively active AKT construct drives collagen contraction and decreases apoptosis. Conclusions TRIP-1 regulates fibroblast acquisition of phenotype and function associated with myofibroblasts. The importance of this finding is it suggests TRIP-1 expression could be a potential target in therapeutic strategy aimed against pathological fibrosis.
    URI
    http://dx.doi.org/10.1186/1465-9921-15-19
    http://hdl.handle.net/10355/41511
    Citation
    Respiratory Research. 2014 Feb 15;15(1):19
    Rights
    Michael F Nyp et al.; licensee BioMed Central Ltd.
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    • BioMed Central Open Access Articles (UMKC)

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