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TRIP-1 via AKT modulation drives lung fibroblast/myofibroblast trans-differentiation
- Source :
- Respiratory Research
- Publisher :
- Springer Nature
-
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.
- Subjects :
- Pulmonary and Respiratory Medicine
Type II TGFβ receptor interacting protein 1 (TRIP-1)
Eukaryotic Initiation Factor-3
α-smooth muscle actin (α-SMA)
Fibrosis
Pulmonary fibrosis
medicine
Animals
Humans
Pulmonary fibroblasts
Fibroblast
Myofibroblasts
Protein kinase B
Lung
Cells, Cultured
Gene knockdown
business.industry
Research
Transfection
Eukaryotic translation initiation factor-3 (eIF3)
Fibroblasts
medicine.disease
Cell biology
Rats
medicine.anatomical_structure
Apoptosis
Immunology
Cell Transdifferentiation
business
Myofibroblast
Proto-Oncogene Proteins c-akt
human activities
Subjects
Details
- Language :
- English
- ISSN :
- 14659921
- Volume :
- 15
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Respiratory Research
- Accession number :
- edsair.doi.dedup.....ca95d84721cef003df885e7bc76cd90e
- Full Text :
- https://doi.org/10.1186/1465-9921-15-19