Nigel Swanson

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)-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.

Inclusion body myositis : investigation of the mumps virus hypothesis by polymerase chain reaction

Inclusion body myositis (IBM) is a distinctive form of chronic inflammatory myopathy characterized pathologically by the finding of rimmed vacuoles and 15–18nm microtubular filamentous inclusions in muscle fiber nuclei and cytoplasm. The observation that these filaments resembled nucleocapsids of the paramyxovirus group and showed immunoreactivity with mumps virus (MV) antibodies has led to a long‐standing postulate that IBM may be a “slow” mumps infection. We searched for the presence of MV RNA in 34 muscle biopsies (17 frozen and 17 paraffin‐embedded) from 18 patients with IBM and 43 control biopsies (mainly from patients with other forms of inflammatory myopathy) using a polymerase chain reaction (PCR). The MV PCR was shown to be sensitive and specific for MV strains (including J‐L) and the integrity of muscle RNA extracts was confirmed by PCR detection of constitutive Ableson tyrosine kinase mRNA. MV RNA was not found in any biopsy from the IBM group nor any of the control cases. Our results therefore do not support the mumps hypothesis for IBM.

Enterovirus hypothesis for motor neurone disease

EDITOR, — A longstanding hypothesis based on indirect and epidemiological evidence proposes that motor neurone disease is a late consequence of subclinical infection with poliovirus. C J Woodall and colleagues provide supportive evidence for this “enterovirus hypothesis,” reporting the finding of conserved enterovirus sequences in the spinal cords of nine of 13 patients with motor neurone disease when they used conventional polymerase chain reaction and hybridisation; they conclude that these sequences were related to Coxsackie B virus rather than poliovirus.1 The enterovirus hypothesis has also been proposed for idiopathic inflammatory myopathy, and Behan and Behan, from the same group as Woodall and colleagues, have reported finding enterovirus in 56% …