Umapathy Nagavedi Siddaramappa, Gonzales Joyce, Fulzele Sadanand, Kim Kyung-mi, Lucas Rudolf, Verin Alexander Dimitrievich
Vascular Biology Center and Section of Pulmonary and Critical Care Medicine, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
Exp Lung Res. 2012 Jun;38(5):223-32. doi: 10.3109/01902148.2012.673049.
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) occur in approximately 200,000 patients per year. Studies indicate that lung endothelium plays a significant role in ALI. The authors' recent in vitro studies demonstrate a novel mechanism of β-nicotinamide adenine dinucleotide (β-NAD)-induced protection against gram-positive (pneumolysin, PLY) and gram-negative (lipopolysaccharide, LPS) toxin-induced lung endothelial cell (EC) barrier dysfunction. The objective of the current study was to evaluate the protective effect of β-NAD against LPS-induced ALI in mice. C57BL/6J mice were randomly divided into 4 groups: vehicle, β-NAD, LPS, and LPS/β-NAD. After surgery, mice were allowed to recover for 24 hours. Evans blue dye-albumin (EBA) was given through the internal jugular vein 2 hours prior to the termination of the experiments. Upon sacrificing the animals, bronchoalveolar lavage fluid (BALF) was collected and the lungs were harvested. β-NAD treatment significantly attenuated the inflammatory response by means of reducing the accumulation of cells and protein in BALF, blunting the parenchymal neutrophil infiltration, and preventing capillary leak. In addition, the histological examination demonstrated decreased interstitial edema in the LPS/β-NAD specimens, as compared to the LPS-only specimens. The mRNA levels of the anti-inflammatory cytokines were up-regulated in the LPS group treated with β-NAD compared to the LPS-only-treated group. β-NAD treatment down-regulated the mRNA levels of the proinflammatory cytokines. These findings suggest that β-NAD could be investigated as a therapeutic option against bacterial toxin-induced lung inflammation and ALI in mice.
急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）每年在约200,000名患者中发生。研究表明，肺内皮细胞在ALI中起重要作用。作者最近的体外研究证明了β-烟酰胺腺嘌呤二核苷酸（β-NAD）诱导的针对革兰氏阳性（肺炎球菌溶血素，PLY）和革兰氏阴性（脂多糖，LPS）毒素诱导的肺内皮细胞（EC）屏障功能障碍的新机制。本研究的目的是评估β-NAD对小鼠LPS诱导的ALI的保护作用。C57BL/6J小鼠随机分为4组：溶剂对照组、β-NAD组、LPS组和LPS/β-NAD组。手术后，小鼠恢复24小时。在实验结束前2小时通过颈内静脉给予伊文思蓝染料-白蛋白（EBA）。处死动物后，收集支气管肺泡灌洗液（BALF）并摘取肺脏。β-NAD治疗通过减少BALF中细胞和蛋白质的积聚、减轻实质中性粒细胞浸润以及防止毛细血管渗漏，显著减轻了炎症反应。此外，组织学检查显示，与仅LPS组标本相比，LPS/β-NAD组标本的间质水肿减轻。与仅用LPS治疗的组相比，用β-NAD治疗的LPS组中抗炎细胞因子的mRNA水平上调。β-NAD治疗下调了促炎细胞因子的mRNA水平。这些发现表明，β-NAD可作为治疗小鼠细菌性毒素诱导的肺部炎症和ALI的一种治疗选择进行研究。
