Chiharu Ota1,2, Mitsuhiro Yamada3, Naoya Fujino1, Hozumi Motohashi4, Yukiko Tando1, Yusuke Takei1,5, Takaya Suzuki6, Toru Takahashi1,5, Satoshi Kamata1,6, Tomonori Makiguchi3, Mutsuo Yamaya1, Hiroshi Kubo1. 1. a Department of Advanced Preventive Medicine for Infectious Disease , Tohoku University Graduate School of Medicine , 2-1 Seiryoumachi, Aobaku , Sendai , Japan. 2. b Department of Pediatrics , Tohoku University Graduate School of Medicine , 1-1 Seiryoumachi, Aobaku , Sendai , Japan. 3. c Department of Respiratory Medicine , Tohoku University Graduate School of Medicine , 1-1 Seiryoumachi, Aobaku , Sendai , Japan. 4. d Department of Gene Expression Regulation, Institute of Development, Aging and Cancer , Tohoku University , 4-1 Seiryoumachi, Aobaku , Sendai , Japan. 5. e Department of Anesthesiology , Tohoku University Hospital , 1-1 Seiryoumachi, Aobaku , Sendai , Japan. 6. f Department of Thoracic Surgery, Institute of Development, Aging and Cancer , Tohoku University , 4-1 Seiryoumachi, Aobaku , Sendai , Japan.
Abstract
AIM: 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. MATERIALS AND 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.
AIM: 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. MATERIALS AND 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.
Entities:
Keywords:
Alveolar epithelial type II cells; HDAC inhibitor; epithelial-to-mesenchymal transition; pulmonary fibrosis; surfactant protein C
Authors: Richard K Albert; Bradford Smith; Carrie E Perlman; David A Schwartz Journal: Am J Respir Crit Care Med Date: 2019-07-15 Impact factor: 21.405
Authors: Samuel S Valenca; Brittany E Dong; Elizabeth M Gordon; Ramon C Sun; Christopher M Waters Journal: Am J Respir Cell Mol Biol Date: 2022-05 Impact factor: 7.748