Deficiency in the zinc transporter ZIP8 impairs epithelia renewal and enhances lung fibrosis
Paul S. Foster, … , Hock L. Tay, Brian G. Oliver
Paul S. Foster, … , Hock L. Tay, Brian G. Oliver
Published June 1, 2022
Citation Information: J Clin Invest. 2022;132(11):e160595. https://doi.org/10.1172/JCI160595.
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Commentary

Deficiency in the zinc transporter ZIP8 impairs epithelia renewal and enhances lung fibrosis

Abstract

Although aging and lung injury are linked to the development of idiopathic pulmonary fibrosis (IPF), the underlying pathognomonic processes predisposing to fibrotic lesions remain largely unknown. A deficiency in the ability of type 2 alveolar epithelial cell (AEC2) progenitors to regenerate and repair the epithelia has been proposed as a critical factor. In this issue of the JCI, Liang et al. identify a deficiency in the zinc transporter SLC39A8 (ZIP8) in AEC2s and in the subsequent activation of the sirtuin SIRT1 that predisposes to decreased AEC2 renewal capacity and enhanced lung fibrosis in both IPF and aging lungs. Interestingly, the authors demonstrate the efficacy of modulating dietary zinc levels, suggesting the need for clinical trials to evaluate the therapeutic potential of dietary supplementation and the development of pharmacological modulation of the Zn/ZIP8/SIRT1 axis for treatment.

Authors

Paul S. Foster, Hock L. Tay, Brian G. Oliver

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Figure 1

The Zn/ZIP8/SIRT1 axis mediates homeostatic AEC2 progenitor cell renewal and epithelial repair in the lungs.

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The Zn/ZIP8/SIRT1 axis mediates homeostatic AEC2 progenitor cell renewal...
(A) In healthy lungs, the Zn/ZIP8/SIRT1 axis regulates homeostatic zinc, NAD+ levels, and SIRT1 activation and promotes AEC2 progenitor cell renewal and epithelial repair and turnover, and is a negative regulator of excessive extracellular matrix deposition. (B) In IPF and aging lungs, AEC2 zinc and NAD+ levels, ZIP8 transporter activity, and SIRT1 expression are reduced. Reduction of these factors results in impaired AEC2 renewal, decreased epithelial repair, and development of fibrotic lesions. (C) In IPF and aged lungs, dietary zinc supplementation restores the activity of the Zn/ZIP8/SIRT1 axis and NAD+ levels, promoting AEC2 progenitor renewal and inhibiting the development of fibrosis. Pharmacological activation of SIRT1 also restores AEC2 renewal and limits fibrosis.