Suberoylanilide hydroxamic acid: a potential epigenetic therapeutic agent for lung fibrosis?

• Published in: The European respiratory journal Vol. 34; no. 1; pp. 145 - 155
• Main Authors: Wang, Z, Chen, C, Finger, S. N, d/o Kwajah M.M, S, Jung, M, Schwarz, H, Swanson, N, Lareu, R. R, Raghunath, M
• Format: Journal Article
• Language: English
• Published: Leeds Eur Respiratory Soc 01.07.2009; Maney
• Subjects: Actins - metabolism; Anti-Inflammatory Agents - pharmacology; Biological and medical sciences; Cell Line; Cell Proliferation; Collagen - metabolism; Epigenesis, Genetic; Fibroblasts - drug effects; Fibrosis - drug therapy; Fibrosis - genetics; Humans; Hydroxamic Acids - therapeutic use; Immunohistochemistry - methods; Lung - drug effects; Lung - pathology; Matrix Metalloproteinase 1 - metabolism; Medical sciences; Muscle, Smooth - metabolism; Pneumology; Respiratory system : syndromes and miscellaneous diseases; Tissue Inhibitor of Metalloproteinase-1 - biosynthesis; Antifibrotic; Lung disease; Respiratory disease; suberoylanilide hydroxamic acid; Potential; Pulmonary fibrosis; Treatment; Acids; Collagen; histone deacetylase inhibitor; Inhibitor; Histone; Fibroblast; Pneumology
• ISSN: 0903-1936; 1399-3003
• DOI: 10.1183/09031936.00084808

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 (TGF)-beta 1 with or without SAHA. Collagen deposition, alpha-smooth muscle actin (alpha-SMA) expression, matrix metalloproteinase (MMP)1 activity, tissue inhibitor of MMP (TIMP)1 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 TGF-beta 1 effects on all the fibroblast lines by preventing their transdifferentiation into alpha-SMA positive myofibroblasts and increased collagen deposition without inducing apoptosis. However, MMP1 activity and TIMP1 production was modulated without a clear fibrolytic effect. SAHA also inhibited serum-induced proliferation of the fibroblast lines and caused hyperacetylation of alpha-tubulin and histone. Cytokine secretion was inhibited from PBMC and lymphocytes at nonapoptotic concentrations. Taken together, these data demonstrate combined antifibrotic and anti-inflammatory properties of SAHA, suggesting its therapeutic potential for pulmonary fibrosis.