Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034069 (pulmonary fibrosis)
 7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Suberoylanilide hydroxamic acid: a potential epigenetic therapeutic agent for lung fibrosis? 1922 93

Pulmonary fibrosis (PF) is characterized by an increase in the number of fibroblasts and an accumulation of collagen fibers in the extracellular matrix (ECM). The members of the copper-dependent lysyl oxidase (LOX) enzyme family regulate the collagen accumulation in the ECM. Tetrathiomolybdate (TM) is a copper chelator. The present study reported the effect of TM on the expression of LOX proteins (LOX, LOXL1, and LOXL2), collagen digestion enzymes (MMP2 and MMP8), and TIMP1 (a collagenase inhibitor) in PF. The PF in mice was induced by intratracheal bleomycin instillation. Adult mice were divided into four groups: mice dissected after 21 days of the first bleomycin (0.08 mg/kg, single dose) treatment (I) and their controls (II), and mice treated with TM for 1 week (1.2 mg/day/mice for the first 4 days and 0.9 mg/day/mice for the last 3 days) after 14 days of the first bleomycin instillation and dissected in the 21st day of the experiment (III) and their controls (IV). Mice in groups III and IV were fed a low-copper (2 mg/kg) diet during the last 7 days of the experiment. The fibrosis score in the lung was determined under a microscope. The expressions of collagen-I, LOX, MMP, and TIMP1 proteins were analyzed by Western blotting in the lung. Mice lungs with fibrosis were characterized by an overexpression of collagen-I, LOX, MMP, and TIMP1 proteins in addition to an accumulation of collagen fibers. TM treatments significantly regressed the overexpression of these proteins in the fibrotic mice lung. In conclusion, TM treatments can be used for the regression of PF, by decreasing collagen-I protein expression and accumulation.
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PMID:The copper chelator tetrathiomolybdate regressed bleomycin-induced pulmonary fibrosis in mice, by reducing lysyl oxidase expressions. 2534 39