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

被引：66

作者：

Liang, Jiurong ^{[1
,2
]}

Huang, Guanling ^{[1
,2
]}

Liu, Xue ^{[1
,2
]}

Taghavifar, Forough ^{[1
,2
]}

Liu, Ningshan ^{[1
,2
]}

Wang, Yizhou ^{[3
]}

Deng, Nan ^{[3
]}

Yao, Changfu ^{[1
,2
]}

Xie, Ting ^{[1
,2
]}

Kulur, Vrishika ^{[1
,2
]}

Dai, Kristy ^{[1
,2
]}

Burman, Ankita ^{[1
,2
]}

Rowan, Simon C. ^{[1
,2
]}

Weigt, S. Samuel ^{[4
]}

Belperio, John ^{[4
]}

Stripp, Barry ^{[1
,2
]}

Parks, William C. ^{[1
,2
,5
]}

Jiang, Dianhua ^{[1
,2
,5
]}

Noble, Paul W. ^{[1
,2
]}

机构：

[1] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA

[2] Cedars Sinai Med Ctr, Womens Guild Lung Inst, Los Angeles, CA 90048 USA

[3] Cedars Sinai Med Ctr, Genom Core, Los Angeles, CA 90048 USA

[4] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA

[5] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2022年 / 132卷 / 11期

关键词：

ENDOPLASMIC-RETICULUM STRESS; STEM-CELLS; LUNG INJURY; ZINC; MECHANISMS; SIRT1; HOMEOSTASIS; APOPTOSIS; SIRTUINS; BIOLOGY;

D O I：

10.1172/JCI157338

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：16

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