ID | 114694 |
タイトル別表記 | 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
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著者 |
竹﨑, 彰夫
徳島大学大学院医科学教育部(医学専攻)
Setoguchi, Yasuhiro
Tokyo Medical University|Tokyo Medical and Dental University
Ledford, Julie G.
University of Arizona
Hosomichi, Kazuyoshi
Kanazawa University
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キーワード | idiopathic pulmonary fibrosis
SFTPA1 mutation
typeⅡ alveolar epithelial cell
necroptosis
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資料タイプ |
学位論文
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抄録 | 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.
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掲載誌名 |
Journal of Experimental Medicine
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ISSN | 15409538
00221007
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cat書誌ID | AA12119243
AA00697559
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出版者 | Rockefeller University Press
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巻 | 216
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号 | 12
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開始ページ | 2724
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終了ページ | 2735
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発行日 | 2019-10-10
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備考 | 内容要旨・審査要旨・論文本文の公開
本論文は,著者Akio Takezakiの学位論文として提出され,学位審査・授与の対象となっている。 |
権利情報 | © 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/).
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EDB ID | |
出版社版DOI | |
出版社版URL | |
フルテキストファイル | |
言語 |
eng
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著者版フラグ |
博士論文全文を含む
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文科省報告番号 | 甲第3426号
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学位記番号 | 甲医第1457号
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学位授与年月日 | 2020-04-23
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学位名 |
博士(医学)
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学位授与機関 |
徳島大学
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部局 |
医学系
病院
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