title: Nicotinamide exacerbates hypoxemia in ventilator-induced lung injury independent of neutrophil infiltration.
abstract: BACKGROUND
  Ventilator-induced lung injury is a form of acute lung injury that develops in critically ill patients on mechanical ventilation and has a high degree of mortality. Nicotinamide phosphoribosyltransferase is an enzyme that is highly upregulated in ventilator-induced lung injury and exacerbates the injury when given exogenously. Nicotinamide (vitamin B3) directly inhibits downstream pathways activated by Nicotinamide phosphoribosyltransferase and is protective in other models of acute lung injury.
  
  
  METHODS
  We administered nicotinamide i.p. to mice undergoing mechanical ventilation with high tidal volumes to study the effects of nicotinamide on ventilator-induced lung injury. Measures of injury included oxygen saturations and bronchoalveolar lavage neutrophil counts, protein, and cytokine levels. We also measured expression of nicotinamide phosophoribosyltransferase, and its downstream effectors Sirt1 and Cebpa, Cebpb, Cebpe. We assessed the effect of nicotinamide on the production of nitric oxide during ventilator-induced lung injury. We also studied the effects of ventilator-induced lung injury in mice deficient in C/EBPε.
  
  
  RESULTS
  Nicotinamide treatment significantly inhibited neutrophil infiltration into the lungs during ventilator-induced lung injury, but did not affect protein leakage or cytokine production. Surprisingly, mice treated with nicotinamide developed significantly worse hypoxemia during mechanical ventilation. This effect was not linked to increases in nitric oxide production or alterations in expression of Nicotinamide phosphoribosyl transferase, Sirt1, or Cebpa and Cebpb. Cebpe mRNA levels were decreased with either nicotinamide treatment or mechanical ventilation, but mice lacking C/EBPε developed the same degree of hypoxemia and ventilator-induced lung injury as wild-type mice.
  
  
  CONCLUSIONS
  Nicotinamide treatment during VILI inhibits neutrophil infiltration of the lungs consistent with a strong anti-inflammatory effect, but paradoxically also leads to the development of significant hypoxemia. These findings suggest that pulmonary neutrophilia is not linked to hypoxemia in ventilator-induced lung injury, and that nicotinamide exacerbates hypoxemia during VILI.
authors: Division of Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
authors: Heather D
authors: HD
authors: Jones
authors: Division of Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
authors: Jeena
authors: J
authors: Yoo
authors: Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
authors: Timothy R
authors: TR
authors: Crother
authors: Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
authors: Pierre
authors: P
authors: Kyme
authors: Pituitary Center, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA, United States of America.
authors: Anat
authors: A
authors: Ben-Shlomo
authors: Pituitary Center, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA, United States of America.
authors: Ramtin
authors: R
authors: Khalafi
authors: Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
authors: Ching W
authors: CW
authors: Tseng
authors: Division of Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
authors: William C
authors: WC
authors: Parks
authors: Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
authors: Moshe
authors: M
authors: Arditi
authors: Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
authors: George Y
authors: GY
authors: Liu
authors: Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
authors: Kenichi
authors: K
authors: Shimada
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018893:Bronchoalveolar Lavage; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D005260:Female; D000860:Hypoxia / Q000139:chemically induced; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009536:Niacinamide / Q000008:administration & dosage* / Q000009:adverse effects; D055397:Ventilator-Induced Lung Injury / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; D022762:CCAAT-Enhancer-Binding Proteins; C489468:Cebpe protein, mouse; D009536:Niacinamide