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

Abstract

BackgroundVentilator-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.MethodsWe 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.ResultsNicotinamide 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.ConclusionsNicotinamide 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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“…However, it also paradoxically led to the development of significant hypoxemia. 20 Vitamin B6 is also needed in protein metabolism and it participates in over 100 reactions in body tissues. In addition, it also plays important role in body immune function as well.…”

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“…A note of caution is appropriate here. In a mouse model of acute lung injury induced by mechanical ventilation, NAM was reported [ 88 ] to cause hypoxemia, yet no such effect of NAM was observed in other studies referenced by these authors [ 88 ] with other models of inflammatory diseases, including acute lung injury, in mice, rats and hamsters. As stated above, NAM abrogates lung injury caused by ischaemia/reperfusion [ 80 ].…”

“…As stated above, NAM abrogates lung injury caused by ischaemia/reperfusion [ 80 ]. Jones et al [ 88 ] did not specify the mouse strain(s), which included the C57, used in their various experiments. Mouse strains are known to differ in their response to immune insults, with the C57BL being the most vulnerable [ 89 ].…”

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“…[15] In one study done on mice, nicotinamide was associated with hypoxemia in VILI, but even they mentioned that neutrophil-induced lung injury was reduced due to niacin supplementation. [16]…”