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Am J Respir Cell Mol Biol ; 51(2): 223-8, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24588101

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.


Subject(s)
Acrylamides/pharmacology , Anti-Inflammatory Agents/pharmacology , Cytokines/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Lung/drug effects , Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors , Piperidines/pharmacology , Pneumonia/drug therapy , Respiratory Distress Syndrome/drug therapy , Ventilator-Induced Lung Injury/drug therapy , Animals , Apoptosis/drug effects , Bronchoalveolar Lavage Fluid/immunology , Caspase 3/metabolism , Cytokines/metabolism , Disease Models, Animal , Inflammation Mediators/metabolism , Lung/enzymology , Lung/immunology , Lung/pathology , Mice , Mice, Inbred C57BL , NAD/metabolism , Neutrophils/drug effects , Neutrophils/enzymology , Neutrophils/immunology , Nicotinamide Phosphoribosyltransferase/metabolism , Pneumonia/enzymology , Pneumonia/immunology , Pneumonia/pathology , Respiratory Distress Syndrome/enzymology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , Ventilator-Induced Lung Injury/enzymology , Ventilator-Induced Lung Injury/immunology , Ventilator-Induced Lung Injury/pathology
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