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 exacerb...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4395431?pdf=render |
| _version_ | 1811207868970434560 |
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| author | Heather D Jones Jeena Yoo Timothy R Crother Pierre Kyme Anat Ben-Shlomo Ramtin Khalafi Ching W Tseng William C Parks Moshe Arditi George Y Liu Kenichi Shimada |
| author_facet | Heather D Jones Jeena Yoo Timothy R Crother Pierre Kyme Anat Ben-Shlomo Ramtin Khalafi Ching W Tseng William C Parks Moshe Arditi George Y Liu Kenichi Shimada |
| author_sort | Heather D Jones |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T04:12:07Z |
| format | Article |
| id | doaj.art-840aa11d64a1475e8137267350b4f78c |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T04:12:07Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-840aa11d64a1475e8137267350b4f78c2022-12-22T03:48:29ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01104e012346010.1371/journal.pone.0123460Nicotinamide exacerbates hypoxemia in ventilator-induced lung injury independent of neutrophil infiltration.Heather D JonesJeena YooTimothy R CrotherPierre KymeAnat Ben-ShlomoRamtin KhalafiChing W TsengWilliam C ParksMoshe ArditiGeorge Y LiuKenichi ShimadaBACKGROUND: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.http://europepmc.org/articles/PMC4395431?pdf=render |
| spellingShingle | Heather D Jones Jeena Yoo Timothy R Crother Pierre Kyme Anat Ben-Shlomo Ramtin Khalafi Ching W Tseng William C Parks Moshe Arditi George Y Liu Kenichi Shimada Nicotinamide exacerbates hypoxemia in ventilator-induced lung injury independent of neutrophil infiltration. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC4395431?pdf=render |
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