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01.12.2014 | Research | Ausgabe 1/2014 Open Access

Respiratory Research 1/2014

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

Zeitschrift:
Respiratory Research > Ausgabe 1/2014
Autoren:
Michael F Nyp, Angels Navarro, Mohammad H Rezaiekhaligh, Ricardo E Perez, Sherry M Mabry, Ikechukwu I Ekekezie
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1465-9921-15-19) contains supplementary material, which is available to authorized users.

Competing interests

The authors have no competing interests.

Authors’ contributions

MFN Interpreted results of experiments, drafted manuscript, edited and revised manuscript, approved final version of manuscript. AN Performed experiments, analyzed data, interpreted results of experiments, prepared figures, edited and revised manuscript, approved final version of manuscript. MHR Performed experiments and approved final version of manuscript. REP Performed experiments and approved final version of manuscript. SMM Performed experiments, edited and revised manuscript, approved final version of manuscript. IIE Conception and design of research, analyzed data, interpreted results of experiments, edited and revised manuscript, approved final version of manuscript.

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.
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