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The ZIP8/SIRT1 axis regulates alveolar progenitor cell renewal in aging and idiopathic pulmonary fibrosis.

Authors :
Liang J
Huang G
Liu X
Taghavifar F
Liu N
Wang Y
Deng N
Yao C
Xie T
Kulur V
Dai K
Burman A
Rowan SC
Weigt SS
Belperio J
Stripp B
Parks WC
Jiang D
Noble PW
Source :
The Journal of clinical investigation [J Clin Invest] 2022 Jun 01; Vol. 132 (11).
Publication Year :
2022

Abstract

Type 2 alveolar epithelial cells (AEC2s) function as progenitor cells in the lung. We have shown previously that failure of AEC2 regeneration results in progressive lung fibrosis in mice and is a cardinal feature of idiopathic pulmonary fibrosis (IPF). In this study, we identified deficiency of a specific zinc transporter, SLC39A8 (ZIP8), in AEC2s from both IPF lungs and lungs of old mice. Loss of ZIP8 expression was associated with impaired renewal capacity of AEC2s and enhanced lung fibrosis. ZIP8 regulation of AEC2 progenitor function was dependent on SIRT1. Replenishment with exogenous zinc and SIRT1 activation promoted self-renewal and differentiation of AEC2s from lung tissues of IPF patients and old mice. Deletion of Zip8 in AEC2s in mice resulted in impaired AEC2 renewal, increased susceptibility to bleomycin injury, and development of spontaneous lung fibrosis. Therapeutic strategies to restore zinc metabolism and appropriate SIRT1 signaling could improve AEC2 progenitor function and mitigate ongoing fibrogenesis.

Details

Language :
English
ISSN :
1558-8238
Volume :
132
Issue :
11
Database :
MEDLINE
Journal :
The Journal of clinical investigation
Publication Type :
Academic Journal
Accession number :
35389887
Full Text :
https://doi.org/10.1172/JCI157338