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 language | English (US) |
|---|---|
| Pages (from-to) | 139-146 |
| Number of pages | 8 |
| Journal | Thorax |
| Volume | 67 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 1 2012 |
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ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
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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 journal › Article
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
Y1 - 2012/1/1
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.
AB - 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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U2 - 10.1136/thoraxjnl-2011-200717
DO - 10.1136/thoraxjnl-2011-200717
M3 - Article
VL - 67
SP - 139
EP - 146
JO - Thorax
JF - Thorax
SN - 0040-6376
IS - 2
ER -