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Epigenetic regulation of myofibroblast differentiation and extracellular matrix production in nasal polyp‐derived fibroblasts
Author(s) -
Cho J.S.,
Moon Y.M.,
Park I.H.,
Um J.Y.,
Moon J.H.,
Park S.J.,
Lee S. H.,
Kang H. J.,
Lee H.M.
Publication year - 2012
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/j.1365-2222.2011.03931.x
Subject(s) - myofibroblast , trichostatin a , extracellular matrix , microbiology and biotechnology , histone deacetylase , chemistry , nasal polyps , histone deacetylase 2 , histone deacetylase inhibitor , cancer research , pathology , histone , biology , immunology , fibrosis , medicine , biochemistry , gene
Summary Background Nasal polyposis is a multi‐factorial disease associated with chronic inflammatory condition of the paranasal sinuses. Myofibroblast differentiation and extracellular matrix ( ECM ) accumulation are involved in the pathogenesis of nasal polyposis. Objective The aim of this study was to study the effect of trichostatin A ( TSA ), a histone deacetylase ( HDAC ) inhibitor, on transforming growth factor ( TGF )‐β1‐induced myofibroblast differentiation and ECM accumulation in nasal polyp‐derived fibroblasts ( NPDF s). Methods Nasal polyp‐derived fibroblasts were isolated from nasal polyps of patients who have chronic rhinosinusitis with nasal polyp. TSA was treated in TGF ‐β1‐induced NPDF s. Expression levels of HDAC 2, α‐smooth muscle actin ( SMA ), TGF ‐β1, collagen type I, acetylated Histone H3, acetylated Histone H4, phosphorylated Smad2/3 and Smad7 were determined by RT ‐ PCR , western blot and/or immunofluorescent staining. The total collagen amount production was analysed by Sircol soluble collagen assay and contractile activity was measured by collagen gel contraction assay. HDAC 2 inhibition by TSA or HDAC 2 silencing was established by RT ‐ PCR and western blot. The epigenetic effect on α‐ SMA gene inactivation was examined by chromatin immunoprecipitation assay. Proliferation was determined by Ki67‐positive cell staining and cytotoxicity was assessed by 3‐(4,5‐ dimethylthiazol‐2yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide ( MTT ) assay. Results The expression levels of HDAC 2, α‐ SMA and TGF ‐β1 were increased in nasal polyp tissues compared to normal inferior turbinate tissues. TSA and HDAC 2 silencing inhibited expression levels α‐ SMA , collagen and HDAC 2. TSA induced hyperacetylation of histone and suppressed opening of α‐ SMA gene promoter in TGF ‐β1‐induced NPDF s. TSA inhibited TGF ‐β1‐induced Smad 2/3 and rescued TGF ‐β1‐suppressed Smad7 signalling pathway. Finally, TSA blocked proliferation in TGF ‐β1‐induced NPDF s and has no cytotoxic effect in NPDF s. Conclusions and Clinical Relevance These results suggest that HDAC inhibition is associated with myofibroblast differentiation and extracelluar matrix accumulation in nasal polyposis. TSA may be useful as an inhibitor of nasal polyp growth, and thus has potential to be used as a novel treatment option for nasal polyposis.

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