Proteasomal inhibition after injury prevents fibrosis by modulating TGF-β1 signalling

Gökhan M. Mutlu, GR Scott Budinger*, Minghua Wu, Anna P Lam, Aaron Zirk, Stephanie Rivera, Daniela Urich, Sergio E. Chiarella, Leonard H.T. Go, Asish K Ghosh, Moises Selman, Annie Pardo, John Varga, David William Kamp, Navdeep Chandel, Jacob I Sznajder, Manu Jain

*Corresponding author for this work

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Background: The development of organ fibrosis after injury requires activation of transforming growth factor b1 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-β1-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-β1-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.

Original languageEnglish (US)
Pages (from-to)139-146
Number of pages8
JournalThorax
Volume67
Issue number2
DOIs
StatePublished - Jan 1 2012

Fingerprint

Fibrosis
Lung
Wounds and Injuries
Skin
Fibroblasts
Idiopathic Pulmonary Fibrosis
Peroxisome Proliferator-Activated Receptors
Bleomycin
Proteasome Inhibitors
Transforming Growth Factors
Cytoplasmic and Nuclear Receptors
Liver Cirrhosis
Bone Marrow
Kidney
Gene Expression
Bortezomib
Genes

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Mutlu, Gökhan M. ; Budinger, GR Scott ; Wu, Minghua ; Lam, Anna P ; Zirk, Aaron ; Rivera, Stephanie ; Urich, Daniela ; Chiarella, Sergio E. ; Go, Leonard H.T. ; Ghosh, Asish K ; Selman, Moises ; Pardo, Annie ; Varga, John ; Kamp, David William ; Chandel, Navdeep ; Sznajder, Jacob I ; Jain, Manu. / Proteasomal inhibition after injury prevents fibrosis by modulating TGF-β1 signalling. In: Thorax. 2012 ; Vol. 67, No. 2. pp. 139-146.
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Proteasomal inhibition after injury prevents fibrosis by modulating TGF-β1 signalling. / Mutlu, Gökhan M.; Budinger, GR Scott; Wu, Minghua; Lam, Anna P; Zirk, Aaron; Rivera, Stephanie; Urich, Daniela; Chiarella, Sergio E.; Go, Leonard H.T.; Ghosh, Asish K; Selman, Moises; Pardo, Annie; Varga, John; Kamp, David William; Chandel, Navdeep; Sznajder, Jacob I; Jain, Manu.

In: Thorax, Vol. 67, No. 2, 01.01.2012, p. 139-146.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Proteasomal inhibition after injury prevents fibrosis by modulating TGF-β1 signalling

AU - Mutlu, Gökhan M.

AU - Budinger, GR Scott

AU - Wu, Minghua

AU - Lam, Anna P

AU - Zirk, Aaron

AU - Rivera, Stephanie

AU - Urich, Daniela

AU - Chiarella, Sergio E.

AU - Go, Leonard H.T.

AU - Ghosh, Asish K

AU - Selman, Moises

AU - Pardo, Annie

AU - Varga, John

AU - Kamp, David William

AU - Chandel, Navdeep

AU - Sznajder, Jacob I

AU - Jain, Manu

PY - 2012/1/1

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N2 - Background: The development of organ fibrosis after injury requires activation of transforming growth factor b1 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-β1-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-β1-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.

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