Suberoylanilide hydroxamic acid: a  potential epigenetic therapeutic agent for  lung fibrosis?
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.
Wang
Z
Z
Tissue Modulation Laboratory, Division of Bioengineering, Faculty of Engineering, National University of Singapore, Singapore.
Chen
C
C
Finger
S N
SN
Kwajah
S
S
Jung
M
M
Schwarz
H
H
Swanson
N
N
Lareu
F F
FF
Raghunath
M
M
D000199:Actins / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D007150:Immunohistochemistry / Q000379:methods; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D009130:Muscle, Smooth / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D000077337:Vorinostat
D000199:Actins; D000893:Anti-Inflammatory Agents; D006877:Hydroxamic Acids; D019715:Tissue Inhibitor of Metalloproteinase-1; D000077337:Vorinostat; D003094:Collagen; D020781:Matrix Metalloproteinase 1