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-kB 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 (TNFa, IL-6, IL-1a), 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. Keywords: apoptosis; FK-866; nicotinamide phosphoribosyltransferase; polymorphonuclear neutrophil; vascular endothelium Clinical RelevanceWe previously identified NAMPT as a candidate gene promoting both acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI). We now further define the role of intracellular nicotinamide phosphoribosyltransferase (NAMPT) activity in the pathogenesis of ARDS/VILI using the selective intracellular NAMPT inhibitor FK-866. These findings support intracellular NAMPT inhibition via FK-866 as a novel therapeutic agent for ARDS via enhanced apoptosis in inflammatory polymorphonuclear neutrophils.Acute respiratory distress syndrome (ARDS) is a devastating inflammatory lung syndrome characterized by diffuse alveolar infiltration, hypoxemia, and respiratory failure that develops in response to a variety of local and systemic insults (e.g., sepsis, pneumonia, and trauma). Hallmarks of ARDS include profound inflammation, deranged alveolar capillary permeability, leukocyte extravasation, spatial heterogeneity, and lung edema, which contribute to multiorgan dysfunction and increased mortality. The exposure to mechanical stress via mechanical ventilation, a supportive intervention strategy for severe respiratory failure, also contributes to multiorgan dysfunction and ARDS mortality.We and others have previously demonstrated that the circulating cytozyme pre-B-cell colony enhancing factor (NAMPT) is a biomarker in sepsis and sepsis-induced ARDS with genetic variants conferring ARDS susceptibility (1-3).

The NAMPT Promoter Is Regulated by Mechanical Stress, Signal Transducer and Activator of Transcription 5, and Acute Respiratory Distress Syndrome–Associated Genetic Variants

“…The genetic association of NAMPT promoter SNPs with ARDS was replicated in a separate ARDS cohort and was found to be associated with the number of ventilator-free days and overall ARDS mortality (12). Finally, novel ARDS therapeutic strategies designed to reduce NAMPT enzymatic activity or bioavailability in preclinical models of ARDS and VILI resulted in significant VILI protection (11,13). These studies, highlighting the intimate involvement of NAMPT activity/expression in ARDS/VILI susceptibility and severity, led us to explore the molecular regulation of NAMPT promoter activity.…”

Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury

“…In this study, we evaluated the effects of imatinib in the well-established murine models of LPS (IT)-and H TV MV (VILI)-induced ALI. As we have previously described, the LPS model is characterized by increased vascular leakage and activation/recruitment of neutrophils to the inflamed lungs (41), whereas the VILI model (VT: 30 ml/kg) is characterized by more modest increases in pulmonary vascular leak and neutrophil lung recruitment (35). To investigate the effects of imatinib on LPS-or VILI-induced alveolar-capillary permeability, we first measured the concentration of protein in BAL.…”

The sensitivity of adipose tissue visfatin mRNA expression to lipopolysaccharide-induced endotoxemia is increased by ovariectomy in female rats

“…In addition, in rats visfatin participates in inflammatory processes in the spleen by modulating both anti-inflammatory and proinflammatory cytokines, such as IL-4, IL-6, TNF, and IL-10, and contributes to apoptosis in the spleen via the mitochondrial pathway [16]. In a study involving rats, the myocardial expression of visfatin increased after the injection of LPS, and the co-administration of a visfatin inhibitor reduced myocardial inflammation and damage and improved cardiac function [14]. Similarly, a visfatin inhibitor attenuated the LPSinduced pulmonary cytokine levels and improved the lung injury scores of mice [15].…”

“…In addition, the central injection of visfatin induces anorectic and febrile responses by enhancing the expression levels of hypothalamic pro-inflammatory cytokines [6], indicating that visfatin might be related to the development of such symptoms in under acute inflammatory conditions. It has been reported that visfatin promotes lung damage and myocardial impairment under acute inflammatory conditions and that the inhibition of visfatin attenuates these disorders [14,15]. In addition, it has been shown that visfatin participates in inflammatory responses in the spleen [16].…”