title: TRIP-1 via AKT modulation drives lung fibroblast/myofibroblast trans-differentiation.
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.
authors: Michael F
authors: MF
authors: Nyp
authors: Angels
authors: A
authors: Navarro
authors: Mohammad H
authors: MH
authors: Rezaiekhaligh
authors: Ricardo E
authors: RE
authors: Perez
authors: Sherry M
authors: SM
authors: Mabry
authors: Department of Pediatrics, Section of Neonatal-Perinatal Medicine, Children's Mercy Hospitals & Clinics, 2401 Gillham Road, 64108 Kansas City, MO, USA. iekekezie@cmh.edu.
authors: Ikechukwu I
authors: II
authors: Ekekezie
mesh_terms: D000818:Animals; D054338:Cell Transdifferentiation / Q000502:physiology*; D002478:Cells, Cultured; D039621:Eukaryotic Initiation Factor-3 / Q000502:physiology*; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D008168:Lung / Q000166:cytology / Q000502:physiology*; D058628:Myofibroblasts / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats
chemical_list: D039621:Eukaryotic Initiation Factor-3; C096013:EIF3I protein, human; D051057:Proto-Oncogene Proteins c-akt