Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis
Introduction and Objectives: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive interstitial lung disease that is refractory to current treatment options. Transforming growth factor (TGF)-β1 is a key pro-fibrotic cytokine that plays a crucial role in IPF pathogenesis. Our group previously...
| Main Authors: | , , , , , |
|---|---|
| Format: | Conference or Workshop Item |
| Published: |
2016
|
| Online Access: | https://eprints.nottingham.ac.uk/38772/ |
| _version_ | 1848795687320289280 |
|---|---|
| author | Brand, Oliver J. Pasini, Alice Habgood, Antony Knox, Alan J. Jenkins, Gisli Pang, Linhua |
| author_facet | Brand, Oliver J. Pasini, Alice Habgood, Antony Knox, Alan J. Jenkins, Gisli Pang, Linhua |
| author_sort | Brand, Oliver J. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Introduction and Objectives: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive interstitial lung disease that is refractory to current treatment options. Transforming growth factor (TGF)-β1 is a key pro-fibrotic cytokine that plays a crucial role in IPF pathogenesis. Our group previously demonstrated distinct epigenetic modifications involved in repression of the antifibrotic gene cyclooxygenase-2 (COX-2) in fibroblasts from IPF (F-IPF) lungs compared with fibroblasts from non-fibrotic lungs (F-NL). Epigenetic drugs capable of inhibiting DNA and histone modifications may, therefore, represent a putative novel therapy. The aim of this study was to investigate the ability of 4 epigenetic inhibitors to regulate TGF-β-driven fibrosis in ex vivo mouse lung.
Methods: A precision-cut lung slice (PCLS) model of fibrosis was established using the previously described [1] CC10-tTS-rtTA-TGFβ1 transgenic (tgTGF-β1) mouse. The model was first assessed by investigating PCLS overexpression of TGF-β1 in response to stimulation of the transgene by doxycycline treatment. Gene expression of COX-2 and fibrotic markers including collagen were assessed after 4 days of treatment. The anti-fibrotic potential of 4 epigenetic inhibitors; BIX01294 (BIX, inhibitor of G9a histone methyltransferase), 3-deazaneplanocin A (DZNep, inhibitor of EZH2 histone methyltransferase), SAHA (inhibitor of histone deacetylases, HDACs) and Decitabine (DAC, DNA demethylating agent) was investigated. Viability of PCLS was assessed by MTT and Prestoblue® viability assay.
Results: Treatment of PCLS from tgTGF-β1 mice with doxycycline induced a concentration-dependent increase in global TGF-β1, pro-fibrotic markers including collagen and pro-inflammatory COX-2, which was comparable to recombinant TGF-β1 treatment. Treatment with three of the epigenetic inhibitors BIX01294, DZNep and DAC did not reduce the pro-fibrotic response following doxycycline treatment. However SAHA demonstrated a significant suppressive effect on COX-2 and collagen expression, while not directly affecting TGF-β1 transgene expression.
Conclusions: The data suggests that SAHA has the potential to reduce fibrosis in a TGF-β1 driven model of pulmonary fibrosis. Further work is currently underway to assess the anti-fibrotic potential of this drug in tgTGF-β1 animals. |
| first_indexed | 2025-11-14T19:36:03Z |
| format | Conference or Workshop Item |
| id | nottingham-38772 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:36:03Z |
| publishDate | 2016 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-387722020-05-04T18:16:32Z https://eprints.nottingham.ac.uk/38772/ Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis Brand, Oliver J. Pasini, Alice Habgood, Antony Knox, Alan J. Jenkins, Gisli Pang, Linhua Introduction and Objectives: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive interstitial lung disease that is refractory to current treatment options. Transforming growth factor (TGF)-β1 is a key pro-fibrotic cytokine that plays a crucial role in IPF pathogenesis. Our group previously demonstrated distinct epigenetic modifications involved in repression of the antifibrotic gene cyclooxygenase-2 (COX-2) in fibroblasts from IPF (F-IPF) lungs compared with fibroblasts from non-fibrotic lungs (F-NL). Epigenetic drugs capable of inhibiting DNA and histone modifications may, therefore, represent a putative novel therapy. The aim of this study was to investigate the ability of 4 epigenetic inhibitors to regulate TGF-β-driven fibrosis in ex vivo mouse lung. Methods: A precision-cut lung slice (PCLS) model of fibrosis was established using the previously described [1] CC10-tTS-rtTA-TGFβ1 transgenic (tgTGF-β1) mouse. The model was first assessed by investigating PCLS overexpression of TGF-β1 in response to stimulation of the transgene by doxycycline treatment. Gene expression of COX-2 and fibrotic markers including collagen were assessed after 4 days of treatment. The anti-fibrotic potential of 4 epigenetic inhibitors; BIX01294 (BIX, inhibitor of G9a histone methyltransferase), 3-deazaneplanocin A (DZNep, inhibitor of EZH2 histone methyltransferase), SAHA (inhibitor of histone deacetylases, HDACs) and Decitabine (DAC, DNA demethylating agent) was investigated. Viability of PCLS was assessed by MTT and Prestoblue® viability assay. Results: Treatment of PCLS from tgTGF-β1 mice with doxycycline induced a concentration-dependent increase in global TGF-β1, pro-fibrotic markers including collagen and pro-inflammatory COX-2, which was comparable to recombinant TGF-β1 treatment. Treatment with three of the epigenetic inhibitors BIX01294, DZNep and DAC did not reduce the pro-fibrotic response following doxycycline treatment. However SAHA demonstrated a significant suppressive effect on COX-2 and collagen expression, while not directly affecting TGF-β1 transgene expression. Conclusions: The data suggests that SAHA has the potential to reduce fibrosis in a TGF-β1 driven model of pulmonary fibrosis. Further work is currently underway to assess the anti-fibrotic potential of this drug in tgTGF-β1 animals. 2016-10-18 Conference or Workshop Item NonPeerReviewed Brand, Oliver J., Pasini, Alice, Habgood, Antony, Knox, Alan J., Jenkins, Gisli and Pang, Linhua (2016) Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis. In: British Thoracic Society Winter Meeting 2016, 7-9 Dec 2016, London, UK. (Unpublished) |
| spellingShingle | Brand, Oliver J. Pasini, Alice Habgood, Antony Knox, Alan J. Jenkins, Gisli Pang, Linhua Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis |
| title | Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis |
| title_full | Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis |
| title_fullStr | Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis |
| title_full_unstemmed | Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis |
| title_short | Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis |
| title_sort | suberanilohydroxamic acid (saha) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (pcls) model of pulmonary fibrosis |
| url | https://eprints.nottingham.ac.uk/38772/ |