β-Nicotinamide adenine dinucleotide attenuates lipopolysaccharide-induced inflammatory effects in a murine model of acute lung injury

Abstract

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.

β-Nicotinamide Adenine Dinucleotide (β-NAD) Inhibits ATP-Dependent IL-1β Release from Human Monocytic Cells

“…We investigated if signaling of β-NAD is mediated via purinergic P2Y1 and/or P2Y11 receptors, as reported previously by several authors for diverse cell types [ 20 , 21 , 25 , 52 , 53 , 54 ]. P2Y1 and P2Y11 receptors are membrane receptors of ATP and β-NAD that, depending on their interacting G proteins, induce diverse signaling cascades.…”

“…P2Y1 and P2Y11 receptors are membrane receptors of ATP and β-NAD that, depending on their interacting G proteins, induce diverse signaling cascades. P2Y1 receptors typically activate phospholipase C and the release of Ca 2+ from intracellular stores, whereas P2Y11 receptors increase both, intracellular Ca 2+ concentrations and cAMP levels [ 51 , 52 , 53 , 54 , 55 ]. Ligand specificity, down-stream signaling and receptor internalization upon agonist binding are modified by heterooligomer formation of P2Y1 and P2Y11 receptors [ 36 , 54 , 56 ].…”

NAD+ protects against EAE by regulating CD4+ T-cell differentiation

“…In addition to its antitumour properties 27 , NAD + may be the ideal molecule to treat autoimmune diseases such as MS, type 1 diabetes and inflammatory bowel disease in which IL-10 has been shown to play a central role 61 . Moreover, NAD + homeostatic properties could be used as therapy beyond autoimmune diseases, including acute and chronic inflammatory diseases 62 .…”

Site‐specific and endothelial‐mediated dysfunction of the alveolar‐capillary barrier in response to lipopolysaccharides

“…In addition, pulmonary microvascular endothelial cell injury and barrier dysfunction lead to the leak of protein‐rich oedema fluid and circulating neutrophils into the pulmonary interstitium and alveolar spaces . On the molecular level increased production of pro‐inflammatory cytokines , such as TNF (tumour necrosis factor), dramatically influences microtubule arrangement in the lung endothelium . Till date, there is no standard treatment to counteract LPS‐mediated oedema, and the complexity of the cell and molecular processes involved in the regulation of the barrier is far from being completely understood.…”