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FASEB J. 2018 Jul;32(7):3583-3596. doi: 10.1096/fj.201701059R. Epub 2018 Feb 8.

Up-regulation of SFTPB expression and attenuation of acute lung injury by pulmonary epithelial cell-specific NAMPT knockdown.

Author information

1
Department of Pediatrics, Children's Mercy, University of Missouri Kansas City School of Medicine, Kansas City, Missouri, USA.
2
Department of Neonatology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
3
Department of Pediatrics, Changsha Central Hospital, Changsha, China.
4
Department of Anesthesiology, Josie Robertson Surgery Center, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, Cornell University, New York, New York, USA.
5
Department of Pediatrics-Anesthesiology, Baylor College of Medicine, Houston, Texas, USA.
6
Department of Biomedical and Health Informatics, Children's Mercy, University of Missouri Kansas City School of Medicine, Kansas City, Missouri, USA.

Abstract

Although a deficiency of surfactant protein B (SFTPB) has been associated with lung injury, SFTPB expression has not yet been linked with nicotinamide phosphoribosyltransferase (NAMPT), a potential biomarker of acute lung injury (ALI). The effects of Nampt in the pulmonary epithelial cell on both SFTPB expression and lung inflammation were investigated in a LPS-induced ALI mouse model. Pulmonary epithelial cell-specific knockdown of Nampt gene expression, achieved by the crossing of Nampt gene exon 2 floxed mice with mice expressing epithelial-specific transgene Cre or by the use of epithelial-specific expression of anti-Nampt antibody cDNA, significantly attenuated LPS-induced ALI. Knockdown of Nampt expression was accompanied by lower levels of bronchoalveolar lavage (BAL) neutrophil infiltrates, total protein and TNF-α levels, as well as lower lung injury scores. Notably, Nampt knockdown was also associated with significantly increased BAL SFTPB levels relative to the wild-type control mice. Down-regulation of NAMPT increased the expression of SFTPB and rescued TNF-α-induced inhibition of SFTPB, whereas overexpression of NAMPT inhibited SFTPB expression in both H441 and A549 cells. Inhibition of NAMPT up-regulated SFTPB expression by enhancing histone acetylation to increase its transcription. Additional data indicated that these effects were mainly mediated by NAMPT nonenzymatic function via the JNK pathway. This study shows that pulmonary epithelial cell-specific knockdown of NAMPT expression attenuated ALI, in part, via up-regulation of SFTPB expression. Thus, epithelial cell-specific knockdown of Nampt may be a potential new and viable therapeutic modality to ALI.-Bi, G., Wu, L., Huang, P., Islam, S., Heruth, D. P., Zhang, L. Q., Li, D.-Y., Sampath, V., Huang, W., Simon, B. A., Easley, R. B., Ye, S. Q. Up-regulation of SFTPB expression and attenuation of acute lung injury by pulmonary epithelial cell-specific NAMPT knockdown.

KEYWORDS:

JNK pathway; gene expression; mouse model; surfactant proteins B

PMID:
29452569
PMCID:
PMC5998971
DOI:
10.1096/fj.201701059R
[Indexed for MEDLINE]

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