A homozygous SFTPA1 mutation drives necroptosis of typeⅡ alveolar epithelial cells in patients with idiopathic pulmonary fibrosis

• Material Type: 博士論文
• Title: A homozygous SFTPA1 mutation drives necroptosis of typeⅡ alveolar epithelial cells in patients with idiopathic pulmonary fibrosis
• Author/Editor: Takezaki, Akio; Tsukumo, Shin-ichi; Setoguchi, Yasuhiro; Ledford, Julie G.; Goto, Hisatsugu; Hosomichi, Kazuyoshi; Uehara, Hisanori; Nishioka, Yasuhiko; Yasutomo, Koji
• Author Heading: Takezaki, Akio; Tsukumo, Shin-ichi; Setoguchi, Yasuhiro; Ledford, Julie G.; Goto, Hisatsugu; Hosomichi, Kazuyoshi; Uehara, Hisanori; Nishioka, Yasuhiko; Yasutomo, Koji
• Publication, Distribution, etc.: Rockefeller University Press
• Publication Date: 2019-10-10
• Publication Date (W3CDTF): 2019-10-10
• Alternative Title: ホモ接合型SFTPA1変異により特発性肺線維症患者のⅡ型肺胞上皮細胞のnecroptosisが亢進する; A mutation in SFTPA1 and pulmonary fibrosis
• Periodical title: Journal of Experimental Medicine
• No. or year of volume/issue: 216 12
• Volume: 216
• Issue: 12
• Pages: 2724-2735
• ISSN (Periodical Title): ISSN : 1540-9538; ISSN : 0022-1007
• Degree grantor/type: 徳島大学
• Date Granted: 2020-04-23
• Dissertation Number: 甲第3426号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: idiopathic pulmonary fibrosis; SFTPA1 mutation; typeⅡ alveolar epithelial cell; necroptosis
• Target Audience: 一般
• Note (General): Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by scattered fibrotic lesions in the lungs. The pathogenesis and genetic basis of IPF remain poorly understood. Here, we show that a homozygous missense mutation in SFTPA1 caused IPF in a consanguineous Japanese family. The mutation in SFTPA1 disturbed the secretion of SFTPA1 protein. Sftpa1 knock-in (Sftpa1-KI) mice that harbored the same mutation as patients spontaneously developed pulmonary fibrosis that was accelerated by influenza virus infection. Sftpa1-KI mice showed increased necroptosis of alveolar epithelial type II (AEII) cells with phosphorylation of IRE1α leading to JNK-mediated up-regulation of Ripk3. The inhibition of JNK ameliorated pulmonary fibrosis in Sftpa1-KI mice, and overexpression of Ripk3 in Sftpa1-KI mice treated with a JNK inhibitor worsened pulmonary fibrosis. These findings provide new insight into the mechanisms of IPF in which a mutation in SFTPA1 promotes necroptosis of AEII cells through JNK-mediated up-regulation of Ripk3, highlighting the necroptosis pathway as a therapeutic target for IPF.
• Format (IMT): application/pdf
• Access Restrictions: インターネット公開
• Rights (production): © 2019 Takezaki et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
• Related Material (DOI): 10.1084/jem.20182351
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ

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