title: Proteasomal inhibition after injury prevents fibrosis by modulating TGF-β(1) signalling.
abstract: BACKGROUND
  The development of organ fibrosis after injury requires activation of transforming growth factor β(1) which regulates the transcription of profibrotic genes. The systemic administration of a proteasomal inhibitor has been reported to prevent the development of fibrosis in the liver, kidney and bone marrow. It is hypothesised that proteasomal inhibition would prevent lung and skin fibrosis after injury by inhibiting TGF-β(1)-mediated transcription.
  
  
  METHODS
  Bortezomib, a small molecule proteasome inhibitor in widespread clinical use, was administered to mice beginning 7 days after the intratracheal or intradermal administration of bleomycin and lung and skin fibrosis was measured after 21 or 40 days, respectively. To examine the mechanism of this protection, bortezomib was administered to primary normal lung fibroblasts and primary lung and skin fibroblasts obtained from patients with idiopathic pulmonary fibrosis and scleroderma, respectively.
  
  
  RESULTS
  Bortezomib promoted normal repair and prevented lung and skin fibrosis when administered beginning 7 days after the initiation of bleomycin. In primary human lung fibroblasts from normal individuals and patients with idiopathic pulmonary fibrosis and in skin fibroblasts from a patient with scleroderma, bortezomib inhibited TGF-β(1)-mediated target gene expression by inhibiting transcription induced by activated Smads. An increase in the abundance and activity of the nuclear hormone receptor PPARγ, a repressor of Smad-mediated transcription, contributed to this response.
  
  
  CONCLUSIONS
  Proteasomal inhibition prevents lung and skin fibrosis after injury in part by increasing the abundance and activity of PPARγ. Proteasomal inhibition may offer a novel therapeutic alternative in patients with dysregulated tissue repair and fibrosis.
authors.affiliation: Department of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Gökhan M
authors.initials: GM
authors.lastname: Mutlu
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.forename: Minghua
authors.initials: M
authors.lastname: Wu
authors.forename: Anna P
authors.initials: AP
authors.lastname: Lam
authors.forename: Aaron
authors.initials: A
authors.lastname: Zirk
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rivera
authors.forename: Daniela
authors.initials: D
authors.lastname: Urich
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Chiarella
authors.forename: Leonard H T
authors.initials: LH
authors.lastname: Go
authors.forename: Asish K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Moises
authors.initials: M
authors.lastname: Selman
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
authors.forename: John
authors.initials: J
authors.lastname: Varga
authors.forename: David W
authors.initials: DW
authors.lastname: Kamp
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
authors.forename: Jacob Iasha
authors.initials: JI
authors.lastname: Sznajder
authors.forename: Manu
authors.initials: M
authors.lastname: Jain
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D001761:Bleomycin; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000378:metabolism; D061988:Proteasome Inhibitors; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D012595:Scleroderma, Systemic / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001897:Boronic Acids; D047495:PPAR gamma; D061988:Proteasome Inhibitors; D011719:Pyrazines; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D000069286:Bortezomib