Nicotinamide phosphoribosyltransferase inhibitor is a novel therapeutic candidate in LPS-induced neutrophil extracellular traps.

Neutrophil extracellular traps (NETs) are beneficial antibacterial defense structures. However, excessive NETs have also been linked to tissue damage and organ dysfunction. LPS and Gram-negative bacteria induce the formation of reactive oxygen species (ROS)-dependent NETs via the JNK pathway. It was found previously that knockdown of nicotinamide phosphoribosyltransferase (NAMPT) upregulates surfactant protein B (SFTPB or SP-B) and attenuates LPS-induced acute lung injury (ALI) via inhibiting JNK activation. This study investigated the effect of FK866, an intracellular NAMPT inhibitor, on the formation of LPS-induced NETs in mouse bronchoalveolar lavage (BAL) neutrophils and in differentiated HL-60 cells. The results show that inhibition of NAMPT by FK866 suppresses NETs formation in BAL neutrophils from the mice exposed to LPS. FK866 also suppresses NETs formation in the differentiated HL-60 cells stimulated with LPS. Additional data indicate that these effects are mediated by suppressing ROS production at least partly via inhibiting JNK activation and depleting NAD(P)H. The utility of inhibition of intracellular NAMPT may be a potential therapy for LPS-induced NETs-related diseases.

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

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.

Neonatal neuron specific enolase, a sensitive biochemical marker of neuronal damage, is increased in preeclampsia: A retrospective cohort study.

BACKGROUND: Preeclampsia leads to chronic intrauterine hypoxia by interfering with placental blood supply. We aimed to investigate whether preeclampsia exposure has an influence on central nervous system of infants, as evaluated by analyzing neonatal serum neuron specific enolase (NSE). METHODS: This was a retrospective study including infants born in Nanfang hospital between Jan 2018 and Feb 2019 without asphyxia. They were divided into normotensive control group and preeclampsia group to compare the NSE levels. Furthermore, PE group was divided into five subgroups by lipstick of urine protein from 0 to 4+ to examine the relationship between urine protein and neonatal NSE. RESULTS: Of the 86 selected neonates, there were 40 in control group and 46 in preeclampsia group. The NSE levels were significantly higher in infants with preeclampsia exposure compared to those infants in control group (45.504 ± 17.926 vs 30.690 ± 4.475, P < 0.0001). Multiple regression analyses revealed that the preeclampsia (ß coef = 0.394, p = 0.041), 4+ proteinuria (ß coef = 0.558, p < 0.0001) and 3+ proteinuria (ß coef = 0.356, p = 0.005) were significant independent variables predicting elevated serum NSE concentration. CONCLUSION: For the first time, this research has suggested the increase of neonatal NSE in preeclampsia, and the quantity of maternal proteinuria may be able to predict neonatal NSE elevation. Long-term neurodevelopmental follow-up and targeted preventive strategies are advised for this underrecognized high-risk population.

The association between hypertensive disorders in pregnancy and bronchopulmonary dysplasia: a systematic review.

BACKGROUND: Whether hypertensive disorders in pregnancy (HDP) are the risk factors of bronchopulmonary dysplasia (BPD) is controversial. A systematic review was made to determine the association between HDP and BPD in preterm infants. METHODS: We searched PubMed, Embase, Cochrane Library, ScienceDirect, Web of Science, with no language limitation, and reviewed the reference lists of the selected articles to identify additional relevant publications and contacted the authors of relevant studies for further information. The data were extracted independently by 2 reviewers who used a predetermined data extraction form. Studies were combined with an odds ratio (OR) using a random-effects model. Meta-regression and subgroup analysis were used to explore potential confounders. Funnel plots, Egger's test and Begg's test were used to investigate the publication bias. The Trim and Fill method was used to control the publication bias. RESULTS: A total of 787 studies were identified and only 15 studies (20 779 patients) were included. The pooled unadjusted OR showed that HDP was significantly associated with BPD (P=0.04; OR=1.29, 95% CI=1.01-1.65). Heterogeneity was substantial (I(2)=74%) and might be partially explained by different variables in maternal complications between the control groups across the studies. The pooled adjusted OR suggested the same conclusion that HDP was a risk factor for BPD (P=0.01; OR=1.59, 95% CI=1.11-2.26). Funnel plot and Egger's test showed that there were publication bias of unadjusted estimate of association between HDP and BPD. CONCLUSIONS: Unadjusted analyses showed that the rate of BPD was slightly higher in the infants exposed to HDP, and adjusted analyses confirmed this finding. But this result should be interpreted cautiously because substantial heterogeneity and publication bias were identified in this review.