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

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

Abstract

Alveolar type II (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 reported that downregulation of NAD+-dependent sirtuin signaling contributes to the impaired progenitor function of IPF AT2 cells. In this study, we identified that a key NAD+ biosynthesis enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is significantly downregulated in IPF AT2 cells. NAMPT deficiency impaired AT2 renewal and enhanced lung fibrosis through downregulation of SIRT7 and SOD2, which results in increased oxidative stress, mitochondrial dysfunction, accumulated aberrant transitional cells, and impaired differentiation from AT2 to alveolar type I (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 wild-type mice. NAMPT activation is a potential promising therapeutic strategy for restoring AT2 progenitor 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 M. Hogaboam, Peter Chen, Barry R. Stripp, Stephen J. Gardell, Dianhua Jiang, Paul W. Noble, Jiurong Liang

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