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 7

NAMPT activation in vivo promotes AT2 regeneration and attenuates lung fibrosis.

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NAMPT activation in vivo promotes AT2 regeneration and attenuates lung f...
(A) Experimental layout: 10- to 12-week old (young) C57BL/6J mice were treated with 20 mg/kg NAT and 2.5 U/kg bleomycin, and lungs were collected on day 5. (B) Flow cytometric gating strategies for lung epithelial and AT2 cells. Epithelial cells were gated as EPCAM+CD31–CD34–CD45– cells among live cells and AT2 cells as CD24–Sca-1– cells within epithelial cell populations. (C–F) Percentages and total cell numbers of epithelial and AT2 cells per lung (n = 5/group; **P < 0.01, by unpaired, 2-tailed Student’s t test). (G) Experimental layout: 10- to 12-week-old (young) C57BL/6J mice were treated with 20 mg/kg NAT (from day –3 to day 3) and 1.25 U/kg bleomycin (day 0), and lungs were collected on day 21. (H) Trichrome staining (scale bars: 500 μm) and (I) hydroxyproline contents (n = 6–10/group; *P < 0.05, by ANOVA) were used to assess collagen deposition. (J) Experimental layout: 10- to 12-week-old (young) C57BL/6J mice were administrated 0.75 U/kg bleomycin (day 0) and treated with 20 mg/kg NAT at the fibrotic stage (days 10–16), and lungs were collected on day 21. (K) Trichrome staining (scale bar: 500 μm) and (L) hydroxyproline in the lungs (n = 4–10/group; *P < 0.05, by 1-way ANOVA) were used to assess fibrosis. (M) Experimental layout: Aged C57BL/6J mice were treated with 20 mg/kg NAT (from day –3 to day 3) and 0.75 U/kg bleomycin (day 0), and lungs were collected on day 21. (N) Trichrome staining (scale bar: 500 μm) and (O) hydroxyproline in the lungs (n = 5–14/group; **P < 0.01, by 1-way ANOVA) were used to assess fibrosis. Boxed areas are shown at higher magnification, scale bars: 500 μm (H, K, and N). Data are shown as the mean ± SEM. All experiments were repeated at least 3 times. Bleo, bleomycin.