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

• Material Type: 博士論文
• ISSN: 1540-9538
• Title: A homozygous SFTPA1 mutation drives necroptosis of typeⅡ alveolar epithelial cells in patients with idiopathic pulmonary fibrosis
• Volume: 216 12
• 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
• Degree grantor/type: 徳島大学
• Date Granted: 2020-04-23
• Date Granted (W3CDTF): 2020-04-23
• Dissertation Number: 甲第3426号
• Degree Type: 博士（医学）
• Conferring No. (Dissertation): 甲第3426号
• 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.
• DOI: info:doi/10.1084/jem.20182351; https://doi.org/info:doi/10.1084/jem.20182351
• Persistent ID (NDL): info:ndljp/pid/11498509; https://dl.ndl.go.jp/pid/11498509
• Collection: 障害者向け資料
• Collection (Materials For Handicapped People:1): テキストデータ
• Collection (particular): 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文; https://dl.ndl.go.jp/collections/A00014
• Acquisition Basis: 博士論文（自動収集）
• Date Accepted (W3CDTF): 2020-06-07T00:39:19+09:00
• Format (IMT): application/pdf
• Access Restrictions: 国立国会図書館内限定公開
• Service for the Digitized Contents Transmission Service: 図書館・個人送信対象外
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• Periodical Title (URI): http://repo.lib.tokushima-u.ac.jp/114694
• Data Provider (Database): 国立国会図書館 : 国立国会図書館デジタルコレクション; https://dl.ndl.go.jp