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ID 114694
Title Alternative
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
Author
Takezaki, Akio Tokushima University
Setoguchi, Yasuhiro Tokyo Medical University|Tokyo Medical and Dental University
Ledford, Julie G. University of Arizona
Hosomichi, Kazuyoshi Kanazawa University
Keywords
idiopathic pulmonary fibrosis
SFTPA1 mutation
typeⅡ alveolar epithelial cell
necroptosis
Content Type
Thesis or Dissertation
Description
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.
Journal Title
Journal of Experimental Medicine
ISSN
15409538
00221007
NCID
AA12119243
AA00697559
Publisher
Rockefeller University Press
Volume
216
Issue
12
Start Page
2724
End Page
2735
Published Date
2019-10-10
Remark
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。
Rights
© 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/).
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3426号
Diploma Number
甲医第1457号
Granted Date
2020-04-23
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Medical Sciences
University Hospital