title: Nicotinamide phosphoribosyltransferase inhibitor is a novel therapeutic candidate in murine models of inflammatory lung injury.
abstract: 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.
authors.affiliation: 1 Institute for Personalized Respiratory Medicine and Department of Medicine, and.
authors.forename: Liliana
authors.initials: L
authors.lastname: Moreno-Vinasco
authors.forename: Hector
authors.initials: H
authors.lastname: Quijada
authors.forename: Saad
authors.initials: S
authors.lastname: Sammani
authors.forename: Jessica
authors.initials: J
authors.lastname: Siegler
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Letsiou
authors.forename: Ryan
authors.initials: R
authors.lastname: Deaton
authors.forename: Laleh
authors.initials: L
authors.lastname: Saadat
authors.forename: Rafe S
authors.initials: RS
authors.lastname: Zaidi
authors.forename: Joe
authors.initials: J
authors.lastname: Messana
authors.forename: Peter H
authors.initials: PH
authors.lastname: Gann
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Machado
authors.forename: Wenli
authors.initials: W
authors.lastname: Ma
authors.forename: Sara M
authors.initials: SM
authors.lastname: Camp
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D053148:Caspase 3 / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011014:Pneumonia / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D055397:Ventilator-Induced Lung Injury / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology
chemical_list: D000178:Acrylamides; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: FK-866; apoptosis; nicotinamide phosphoribosyltransferase; polymorphonuclear neutrophil; vascular endothelium