title: Histone deacetylase inhibitor restores surfactant protein-C expression in alveolar-epithelial type II cells and attenuates bleomycin-induced pulmonary fibrosis in vivo.
abstract: OBJECTIVE
  Surfactant protein-C (SP-C) of alveolar epithelial type II cells (ATII) plays a key role in maintaining alveolar integrity and repair. Mutations or decreased expression of SFTPC, the gene encoding SP-C, causes ATII injury and aberrant repair of the lung tissue to develop pulmonary fibrosis. Histone deacetylases (HDACs) epigenetically remove acetyl groups from acetylated histones and regulate transcription. HDAC inhibitors attenuated epithelial-to-mesenchymal transition (EMT) and fibrotic disorders. The aim of this study is to investigate whether Trichostatin A (TSA), a pan-HDAC inhibitor, epigenetically exerts a protective effect on ATII against fibrotic changes via the restoration of SFTPC expression.
  
  
  METHODS
  We treated A549 cells with TGF-β1 to induce EMT, followed by TSA treatment. We evaluated SFTPC mRNA, histone acetylation levels in the SFTPC gene promoter region, and pro-SP-C protein. C57BL6/J mice were treated with intratracheal bleomycin instillation followed by TSA administration. Histological changes and Sftpc mRNA expression in isolated ATII were evaluated.
  
  
  RESULTS
  TGF-β1 treatment decreased SFTPC mRNA in A549 cells. TSA restored SFTPC mRNA, and increased histone H4 acetylation in the SFTPC promoter region in vitro. The administration of TSA partially attenuated BLM-induced pulmonary fibrosis and increased the Sftpc mRNA expression in isolated ATII from bleomycin-treated lungs in vivo.
  
  
  CONCLUSIONS
  Decreased expression of SFTPC by TGF-β1 treatment was restored by TSA via hyperacetylation of histone H4 in the promoter region. TSA partially attenuated pulmonary fibrosis and increased Sftpc mRNA in ATII. Our findings suggest that the epigenetic restoration of SP-C would be a therapeutic target for pulmonary fibrosis.
authors.affiliation: a Department of Advanced Preventive Medicine for Infectious Disease , Tohoku University Graduate School of Medicine , 2-1 Seiryoumachi, Aobaku , Sendai , Japan.|b Department of Pediatrics , Tohoku University Graduate School of Medicine , 1-1 Seiryoumachi, Aobaku , Sendai , Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Ota
authors.affiliation: c Department of Respiratory Medicine , Tohoku University Graduate School of Medicine , 1-1 Seiryoumachi, Aobaku , Sendai , Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yamada
authors.affiliation: a Department of Advanced Preventive Medicine for Infectious Disease , Tohoku University Graduate School of Medicine , 2-1 Seiryoumachi, Aobaku , Sendai , Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Fujino
authors.affiliation: d Department of Gene Expression Regulation, Institute of Development, Aging and Cancer , Tohoku University , 4-1 Seiryoumachi, Aobaku , Sendai , Japan.
authors.forename: Hozumi
authors.initials: H
authors.lastname: Motohashi
authors.affiliation: a Department of Advanced Preventive Medicine for Infectious Disease , Tohoku University Graduate School of Medicine , 2-1 Seiryoumachi, Aobaku , Sendai , Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Tando
authors.affiliation: a Department of Advanced Preventive Medicine for Infectious Disease , Tohoku University Graduate School of Medicine , 2-1 Seiryoumachi, Aobaku , Sendai , Japan.|e Department of Anesthesiology , Tohoku University Hospital , 1-1 Seiryoumachi, Aobaku , Sendai , Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takei
authors.affiliation: f Department of Thoracic Surgery, Institute of Development, Aging and Cancer , Tohoku University , 4-1 Seiryoumachi, Aobaku , Sendai , Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: a Department of Advanced Preventive Medicine for Infectious Disease , Tohoku University Graduate School of Medicine , 2-1 Seiryoumachi, Aobaku , Sendai , Japan.|e Department of Anesthesiology , Tohoku University Hospital , 1-1 Seiryoumachi, Aobaku , Sendai , Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: a Department of Advanced Preventive Medicine for Infectious Disease , Tohoku University Graduate School of Medicine , 2-1 Seiryoumachi, Aobaku , Sendai , Japan.|f Department of Thoracic Surgery, Institute of Development, Aging and Cancer , Tohoku University , 4-1 Seiryoumachi, Aobaku , Sendai , Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kamata
authors.affiliation: c Department of Respiratory Medicine , Tohoku University Graduate School of Medicine , 1-1 Seiryoumachi, Aobaku , Sendai , Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Makiguchi
authors.affiliation: a Department of Advanced Preventive Medicine for Infectious Disease , Tohoku University Graduate School of Medicine , 2-1 Seiryoumachi, Aobaku , Sendai , Japan.
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Yamaya
authors.affiliation: a Department of Advanced Preventive Medicine for Infectious Disease , Tohoku University Graduate School of Medicine , 2-1 Seiryoumachi, Aobaku , Sendai , Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kubo
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001761:Bleomycin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D037721:Pulmonary Surfactant-Associated Protein C / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D037721:Pulmonary Surfactant-Associated Protein C; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; C012589:trichostatin A
keywords: Alveolar epithelial type II cells; HDAC inhibitor; epithelial-to-mesenchymal transition; pulmonary fibrosis; surfactant protein C