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Nicotinamide Exacerbates Hypoxemia in Ventilator-Induced Lung Injury Independent of Neutrophil Infiltration

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 exacer...

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Autores principales: Jones, Heather D., Yoo, Jeena, Crother, Timothy R., Kyme, Pierre, Ben-Shlomo, Anat, Khalafi, Ramtin, Tseng, Ching W., Parks, William C., Arditi, Moshe, Liu, George Y., Shimada, Kenichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395431/
https://www.ncbi.nlm.nih.gov/pubmed/25875775
http://dx.doi.org/10.1371/journal.pone.0123460
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author Jones, Heather D.
Yoo, Jeena
Crother, Timothy R.
Kyme, Pierre
Ben-Shlomo, Anat
Khalafi, Ramtin
Tseng, Ching W.
Parks, William C.
Arditi, Moshe
Liu, George Y.
Shimada, Kenichi
author_facet Jones, Heather D.
Yoo, Jeena
Crother, Timothy R.
Kyme, Pierre
Ben-Shlomo, Anat
Khalafi, Ramtin
Tseng, Ching W.
Parks, William C.
Arditi, Moshe
Liu, George Y.
Shimada, Kenichi
author_sort Jones, Heather D.
collection PubMed
description 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.
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spelling pubmed-43954312015-04-21 Nicotinamide Exacerbates Hypoxemia in Ventilator-Induced Lung Injury Independent of Neutrophil Infiltration Jones, Heather D. Yoo, Jeena Crother, Timothy R. Kyme, Pierre Ben-Shlomo, Anat Khalafi, Ramtin Tseng, Ching W. Parks, William C. Arditi, Moshe Liu, George Y. Shimada, Kenichi PLoS One Research Article 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. Public Library of Science 2015-04-13 /pmc/articles/PMC4395431/ /pubmed/25875775 http://dx.doi.org/10.1371/journal.pone.0123460 Text en © 2015 Jones et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Jones, Heather D.
Yoo, Jeena
Crother, Timothy R.
Kyme, Pierre
Ben-Shlomo, Anat
Khalafi, Ramtin
Tseng, Ching W.
Parks, William C.
Arditi, Moshe
Liu, George Y.
Shimada, Kenichi
Nicotinamide Exacerbates Hypoxemia in Ventilator-Induced Lung Injury Independent of Neutrophil Infiltration
title Nicotinamide Exacerbates Hypoxemia in Ventilator-Induced Lung Injury Independent of Neutrophil Infiltration
title_full Nicotinamide Exacerbates Hypoxemia in Ventilator-Induced Lung Injury Independent of Neutrophil Infiltration
title_fullStr Nicotinamide Exacerbates Hypoxemia in Ventilator-Induced Lung Injury Independent of Neutrophil Infiltration
title_full_unstemmed Nicotinamide Exacerbates Hypoxemia in Ventilator-Induced Lung Injury Independent of Neutrophil Infiltration
title_short Nicotinamide Exacerbates Hypoxemia in Ventilator-Induced Lung Injury Independent of Neutrophil Infiltration
title_sort nicotinamide exacerbates hypoxemia in ventilator-induced lung injury independent of neutrophil infiltration
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395431/
https://www.ncbi.nlm.nih.gov/pubmed/25875775
http://dx.doi.org/10.1371/journal.pone.0123460
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