The ZIP8/SIRT1 axis regulates alveolar progenitor cell renewal in aging and idiopathic pulmonary fibrosis
Jiurong Liang, Guanling Huang, Xue Liu, Forough Taghavifar, Ningshan Liu, Yizhou Wang, Nan Deng, Changfu Yao, Ting Xie, Vrishika Kulur, Kristy Dai, Ankita Burman, Simon C. Rowan, S. Samuel Weigt, John Belperio, Barry Stripp, William C. Parks, Dianhua Jiang, Paul W. Noble
Jiurong Liang, Guanling Huang, Xue Liu, Forough Taghavifar, Ningshan Liu, Yizhou Wang, Nan Deng, Changfu Yao, Ting Xie, Vrishika Kulur, Kristy Dai, Ankita Burman, Simon C. Rowan, S. Samuel Weigt, John Belperio, Barry Stripp, William C. Parks, Dianhua Jiang, Paul W. Noble
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Research Article Pulmonology

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

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.

Authors

Jiurong Liang, Guanling Huang, Xue Liu, Forough Taghavifar, Ningshan Liu, Yizhou Wang, Nan Deng, Changfu Yao, Ting Xie, Vrishika Kulur, Kristy Dai, Ankita Burman, Simon C. Rowan, S. Samuel Weigt, John Belperio, Barry Stripp, William C. Parks, Dianhua Jiang, Paul W. Noble

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Figure 6

Spontaneous and increased lung fibrosis after bleomycin injury in old Zip8AEC2 mice and zinc metabolism–regulated lung fibrosis.

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Spontaneous and increased lung fibrosis after bleomycin injury in old Zi...
(A) Experimental layout for spontaneous lung fibrosis in 12-month-old Zip8AEC2 and control mice. (B) Trichrome staining of lung sections showed that Zip8AEC2 mice developed fibrosis in subpleural (arrow) and interstitial (arrowheads) regions. Scale bars: top: 1 mm; bottom: 200 μm. (C) Hydroxyproline content (μg per right lung) in the lungs of 12-month-old male Zip8AEC2 (n = 4) and control (n = 5) mice (*P < 0.05). (D) Experimental layout for Zip8AEC2 and control mice treated with bleomycin following tamoxifen injection. (E and F) Survival (E) and hydroxyproline levels (μg per whole lung) (F) of 12-month-old Zip8AEC2 and control mice 21 days after 1.25 U/kg bleomycin treatment (E: n = 16–18, P = 0.33; F: n = 8–10, *P < 0.05). (G and H) Survival (G)and hydroxyproline content (μg per right lung) (H) of 7- to 10-month-old Zip8AEC2 and control mice on day 21 after 2 U/kg bleomycin treatment (G: n = 32, *P < 0.05; H: n = 5–10, *P < 0.05). (I) Experimental layout for WT mice fed low-zinc and control diets and treated with bleomycin for lung fibrosis study. (J) Survival of mice fed low-zinc and control diets on day 14 after bleomycin injury (n = 16–18, P = 0.07). (K) Hydroxyproline content (μg per right lung) of lungs from mice fed low-zinc and control diets on day 21 after bleomycin injury (n = 8–10, *P < 0.05). (L) Experimental layout for WT mice treated with high-zinc and control diets and bleomycin for lung fibrosis study. (M) Hydroxyproline content (μg per right lung) of lungs from mice fed high-zinc and control diets on day 21 after bleomycin injury (n = 5–8, *P < 0.05). Data are shown as mean ± SEM. C, F, H, K, and M: unpaired 2-tailed Student’s t test; E, G, and J: log-rank test.