Nicotinamide phosphoribosyltransferase inhibitor is a novel therapeutic candidate in murine models of inflammatory lung injury.

TitleNicotinamide phosphoribosyltransferase inhibitor is a novel therapeutic candidate in murine models of inflammatory lung injury.
Publication TypeJournal Article
Year of Publication2014
AuthorsMoreno-Vinasco L, Quijada H, Sammani S, Siegler J, Letsiou E, Deaton R, Saadat L, Zaidi RS, Messana J, Gann PH, Machado RF, Ma W, Camp SM, Wang T, Garcia JGN
JournalAm J Respir Cell Mol Biol
Date Published2014 Aug
ISSN Number1535-4989
KeywordsAcrylamides, Animals, Anti-Inflammatory Agents, Apoptosis, Bronchoalveolar Lavage Fluid, Caspase 3, Cytokines, Disease Models, Animal, Enzyme Inhibitors, Inflammation Mediators, Lung, Mice, Mice, Inbred C57BL, NAD, Neutrophils, Nicotinamide Phosphoribosyltransferase, Piperidines, Pneumonia, Respiratory Distress Syndrome, Adult, Ventilator-Induced Lung Injury

<p>We previously identified the intracellular nicotinamide phosphoribosyltransferase (iNAMPT, aka pre-B-cell colony enhancing factor) as a candidate gene promoting acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI) with circulating nicotinamide phosphoribosyltransferase potently inducing NF-κB signaling in lung endothelium. iNAMPT also synthesizes intracellular nicotinamide adenine dinucleotide (iNAD) in response to extracellular oxidative stress, contributing to the inhibition of apoptosis via ill-defined mechanisms. We now further define the role of iNAMPT activity in the pathogenesis of ARDS/VILI using the selective iNAMPT inhibitor FK-866. C57/B6 mice were exposed to VILI (40 ml/kg, 4 h) or LPS (1.5 mg/kg, 18 h) after osmotic pump delivery of FK-866 (100 mg/kg/d, intraperitoneally). Assessment of total bronchoalveolar lavage (BAL) protein, polymorphonuclear neutrophil (PMN) levels, cytokine levels (TNF-α, IL-6, IL-1α), lung iNAD levels, and injury scores revealed that FK-866-mediated iNAMPT inhibition successfully reduced lung tissue iNAD levels, BAL injury indices, inflammatory cell infiltration, and lung injury scores in LPS- and VILI-exposed mice. FK-866 further increased lung PMN apoptosis, as reflected by caspase-3 activation in BAL PMNs. These findings support iNAMPT inhibition via FK-866 as a novel therapeutic agent for ARDS via enhanced apoptosis in inflammatory PMNs.</p>

Alternate JournalAm. J. Respir. Cell Mol. Biol.
PubMed ID24588101
PubMed Central IDPMC4148034
Grant ListR01 HL094394 / HL / NHLBI NIH HHS / United States
R01 HL111656 / HL / NHLBI NIH HHS / United States
HL94394 / HL / NHLBI NIH HHS / United States