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

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.

Novel computational analysis of large transcriptome datasets identifies sets of genes distinguishing chronic obstructive pulmonary disease from healthy lung samples

“…RAC1 is required for airway smooth muscle contraction 40 Selenoprotein H SELENOH Up – URB1 ribosome biogenesis homolog URB1 Up – WD repeat domain 4 WDR4 Up – Chromosome 10 open reading frame 53 C10orf53 Down – Cysteine rich secretory protein 3 CRISP3 Down – Integral membrane protein 2A ITM2A Down – Peroxisomal biogenesis factor 5 like PEX5L Down – RIPOR family member 3 RIPOR3 Down – Secretoglobin family 3A member 2 SCGB3A2 Down Supports lung development, anti-apoptotic 41 , anti-fibrotic 42 , modulates inflammation (mostly anti-inflammatory) 43 , 44 . Gene polymorphisms associated with asthma risk in Asian populations 45 , 46 Surfactant protein B SFTPB Down Anti-inflammatory 47 , 48 , promotes alveolar stability. Gene polymorphisms associated with COPD risk, lung function (FEV1), exacerbation frequency and respiratory failure 49 – 52 .…”

Intranasal Application of Budesonide Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Suppressing Nucleotide-Binding Oligomerization Domain-Like Receptor Family, Pyrin Domain-Containing 3 Inflammasome Activation in Mice

“…Intratracheal ( i.t. ) instillation of lipopolysaccharide (LPS), a bacterial cell wall component, is a common and well-accepted experimental model for ALI in mice [ 6 ].…”

Epigenetic regulation of NfatC1 transcription and osteoclastogenesis by nicotinamide phosphoribosyl transferase in the pathogenesis of arthritis

“…RNA isolation, quantitative RT-PCR, and nascent RNA capture were performed as we previously described 36 .…”