RT Journal Article
SR Electronic
T1 Suberoylanilide hydroxamic acid: a potential epigenetic therapeutic agent for lung fibrosis?
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 145
OP 155
DO 10.1183/09031936.00084808
VO 34
IS 1
A1 Z. Wang
A1 C. Chen
A1 S. N. Finger
A1 S. d/o Kwajah M.M
A1 M. Jung
A1 H. Schwarz
A1 N. Swanson
A1 R. R. Lareu
A1 M. Raghunath
YR 2009
UL http://erj.ersjournals.com/content/34/1/145.abstract
AB 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)-β1 with or without SAHA. Collagen deposition, α-smooth muscle actin (α-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-β1 effects on all the fibroblast lines by preventing their transdifferentiation into α-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 α-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.