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S52 Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis
  1. OJ Brand,
  2. A Pasini,
  3. A Habgood,
  4. AJ Knox,
  5. G Jenkins,
  6. L Pang
  1. University of Nottingham, Nottingham, UK

Abstract

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 described1 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® 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.

Reference

  1. Lee CG, Cho SJ, Kang MJ, et al. Early growth response Gene 1-mediated apoptosis is essential for transforming growth Factor β1-induced pulmonary fibrosis. J Exp Med 2004; 200(3):377–389.

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