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

Liliana Moreno-Vinasco, Hector Quijada, Saad Sammani, Jessica Siegler, Eleftheria Letsiou, Ryan Deaton, Laleh Saadat, Rafe S. Zaidi, Joe Messana, Peter H. Gann, Roberto F. Machado, Wenli Ma, Sara M. Camp, Ting Wang, Joe G.N. Garcia

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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 (TNFα, 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 lungPMNapoptosis, 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.

Original languageEnglish (US)
Pages (from-to)223-228
Number of pages6
JournalAmerican journal of respiratory cell and molecular biology
Volume51
Issue number2
DOIs
StatePublished - Aug 2014

Keywords

  • Apoptosis
  • FK-866
  • Nicotinamide phosphoribosyltransferase
  • Polymorphonuclear neutrophil
  • Vascular endothelium

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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