SAHA- a potential epigenetic therapeutic agent for lung fibrosis?

¹ Tissue Modulation Laboratory, Division of Bioengineering, Faculty of Engineering, National University of Singapore
² Dept of Physiology, National University of Singapore
³ Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg, Germany
⁴ Molecular Hepatology, School of Medicine and Pharmacology, Faculty of Medicine, Dentistry and Heath Sciences, The University of Western Australia
⁵ Tissue Modulation Laboratory, Division of Bioengineering, Faculty of Engineering, National University of Singapore; Molecular Hepatology, School of Medicine and Pharmacology, Faculty of Medicine, Dentistry and Heath Sciences, The University of Western Australia; and NUS Tissue Engineering Program, Dept of Orthopedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore
⁶ Tissue Modulation Laboratory, Division of Bioengineering, Faculty of Engineering, National University of Singapore; and Dept of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore

^* To whom correspondence should be addressed. E-mail: bierm{at}nus.edu.sg.

	Abstract

Pulmonary fibrosis represents a fatal stage of interstitial lung diseases of known and idiopathic aetiology. No effective therapy is currently available. Based on an indication-discovery approach we present novel in vitro evidence that the histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA), an FDA-approved anti-cancer drug, has antifibrotic and anti-inflammatory potential.

Human lung fibroblasts (fetal, adult and idiopathic adult pulmonary fibrosis) were treated with transforming growth factor 1 (TGF1) with or without SAHA. Collagen deposition, -smooth muscle actin (-SMA) expression, matrix metalloproteinase 1 (MMP1) activity, tissue inhibitor of MMPs 1 (TIMP1) production, apoptosis and cell proliferation were assessed. Pro-inflammatory cytokines relevant to pulmonary fibrosis were assayed in SAHA-treated human peripheral blood mononuclear cells (PBMC) and its subpopulations.

SAHA abrogated TGF1 effects on all the fibroblast lines by preventing their transdifferentiation into -SMA positive myofibroblasts and increased collagen deposition without inducing apoptosis. MMP1 activity and TIMP1 production, however, was modulated without a clear fibrolytic effect. SAHA also inhibited serum-induced proliferation of the fibroblast lines and caused hyperacetylation of -tubulin and histone. Cytokine secretion was inhibited from PBMC and lymphocytes at non-apoptotic concentrations.

Taken together, these data demonstrate combined antifibrotic and anti-inflammatory properties of SAHA, suggesting its therapeutic potential for pulmonary fibrosis.