Activation of the impaired NAMPT/SIRT7/SOD2 axis restores alveolar progenitor cell renewal in idiopathic pulmonary fibrosis
Xuexi Zhang, Xue Liu, Yujie Qiao, Anas Rabata, Ningshan Liu, Changfu Yao, Tanyalak Parimon, Danica Chen, Cory Hogaboam, Peter Chen, Barry Stripp, Stephen J. Gardell, Dianhua Jiang, Paul W. Noble, Jiurong Liang
Xuexi Zhang, Xue Liu, Yujie Qiao, Anas Rabata, Ningshan Liu, Changfu Yao, Tanyalak Parimon, Danica Chen, Cory Hogaboam, Peter Chen, Barry Stripp, Stephen J. Gardell, Dianhua Jiang, Paul W. Noble, Jiurong Liang
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Research Article Cell biology Metabolism Pulmonology

Activation of the impaired NAMPT/SIRT7/SOD2 axis restores alveolar progenitor cell renewal in idiopathic pulmonary fibrosis

Abstract

Alveolar type 2 (AT2) progenitor cell exhaustion and impaired regenerative capacity are key pathogenic hallmarks in idiopathic pulmonary fibrosis (IPF). Nicotinamide adenine dinucleotide (NAD+) functions as a central regulator of cellular energy metabolism. We have previously reported that downregulation of NAD+-dependent sirtuin signaling contributes to the impaired progenitor cell function of IPF AT2 cells. In this study, we found that a key NAD+ biosynthesis enzyme, nicotinamide phosphoribosyltransferase (NAMPT), was significantly downregulated in IPF AT2 cells. NAMPT deficiency impaired AT2 renewal and enhanced lung fibrosis through downregulation of SIRT7 and SOD2, which resulted in increased oxidative stress, mitochondrial dysfunction, accumulated aberrant transitional cells, and impaired differentiation from AT2 to alveolar type 1 (AT1) cells. A mouse model with AT2-specific deletion of Nampt showed severely impaired AT2 renewal capacity and increased susceptibility to bleomycin lung injury. Activation of NAMPT by small-molecule activators promoted IPF AT2 renewal and reversed lung fibrosis in WT mice. NAMPT activation is a potentially promising therapeutic strategy for restoring AT2 progenitor cell function and halting or reversing progressive pulmonary fibrosis.

Authors

Xuexi Zhang, Xue Liu, Yujie Qiao, Anas Rabata, Ningshan Liu, Changfu Yao, Tanyalak Parimon, Danica Chen, Cory Hogaboam, Peter Chen, Barry Stripp, Stephen J. Gardell, Dianhua Jiang, Paul W. Noble, Jiurong Liang

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Figure 1

Decreased expression of the NAD+ biosynthesis enzyme NAMPT in IPF AT2 cells.

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Decreased expression of the NAD+ biosynthesis enzyme NAMPT in IPF AT2 ce...
(A) Uniform manifold approximation and projection (UMAP) visualization of epithelial cell types and NAMPT expression in healthy and IPF lung cells in the in-house scRNA-seq dataset. PNEC, pulmonary neuroendocrine cells. (B) UMAP visualization of NAMPT expression in AT2 cells from healthy and IPF lungs. (C and D) Violin plots showing NAMPT expression levels in AT2 cells from in-house (C) and recently published scRNA-seq datasets (D). (E) Real-time PCR analysis of NAMPT expression in freshly isolated AT2 cells from healthy and IPF lungs (n = 5–6/group; **P < 0.01, by unpaired, 2-tailed Student’s t test). (F) Single-cell Western blot analysis of NAMPT expression in freshly isolated AT2 cells from healthy and IPF lungs, with β-tubulin used as a loading control (****P < 0.0001, by 1-way ANOVA). (G) Western blot analysis and quantification of NAMPT expression in immortalized AT2 cells from healthy and IPF donors. GAPDH served as a loading control (n = 3/group; ***P < 0.001, by unpaired, 2-tailed Student’s t test). (H) Costaining of NAMPT (red) and HTII-280 (green, an AT2 marker) of healthy and IPF lung sections. The staining was performed with lung sections from 3 patients with IPF and 3 healthy donors. Representative cells (asterisks) are shown at higher magnification. Scale bars: 20 μm. Insets, original magnification, ×63. (I) Quantification of NAMPT staining (relative signal intensity) in individual AT2 cells (HTII-280+), shown as violin plots with median and quartiles (n = 50–60 cells/section, n = 3/group; ****P < 0.0001, by unpaired, 2-tailed Student’s t test). Data are shown as the mean ± SEM. All experiments were repeated at least 3 times.