SESSION TYPE: New Insights into ARDS/Lung Injury
PRESENTED ON: Monday, October 22, 2012 at 04:00 PM - 05:30 PM
PURPOSE: Acute Respiratory Distress Syndrome (ARDS) is a clinical syndrome of acute lung failure characterized by inflammation and tissue damage. The pro-inflammatory molecule nicotinamide adenine phosphoribosyltranferase (NAMPT) is strongly implicated in the ventilator-induced lung injury (VILI) model of ARDS; nicotinamide (NAM, also known as Vitamin B3) is a direct inhibitor of NAMPT-induced pathways. We hypothesized that exogenous administration of NAM would inhibit NAMPT-induced inflammation in the lung during VILI and improve survival.
METHODS: We used a mouse model of high-tidal volume mechanical ventilation (20 cc/kg) to induce lung injury. NAM (400 mg/kg) or PBS was injected intraperitoneally after 1 hour of mechanical ventilation, and ventilation was continued for a total of 6 hours. Bronchoalveolar lavage fluid (BALF) protein, cytokines, polymorphonuclear neutrophil (PMN) levels, and serum protein levels were assessed. In other animals, Evans blue dye was injected via tail vein 2.5 hours prior to euthanasia to assess vascular leakage. In a separate survival experiment, mice were treated with NAM or PBS and ventilated for 18 hours and observed for mortality.
RESULTS: NAM administration significantly decreased neutrophils (87% reduction, p < .05) in BALF compared with PBS controls, but did not affect IL-6, IL-1β, or KC concentrations and had no effect on vascular leakage or BALF/serum protein ratios. In a survival experiment, NAM administration adversely affected survival (p < .05) although a significant reduction (85%, p < .05) in BALF PMNs in NAM-treated mice was again noted; surprisingly, increased numbers of PMNs in BALF was associated with increased survival on mechanical ventilation (p < .05).
CONCLUSIONS: NAM administration significantly inhibits neutrophil recruitment to the lung during VILI. However, NAM has no effect on vascular leakage and worsens survival. These data suggest that neutrophil infiltration of alveoli in VILI may be independent of injury and mortality. NAM’s deleterious effects on survival may be related to its effects on NAMPT-regulated pathways.
CLINICAL IMPLICATIONS: The role of NAMPT in ARDS remains unclear, and NAM administration might have unforeseen deleterious consequences in acute lung injury.
DISCLOSURE: The following authors have nothing to disclose: Heather Jones, Pierre Kyme, Timothy Crother, George Liu, Moshe Arditi
No Product/Research Disclosure InformationCedars-Sinai Medical Center, Los Angeles, CA