Nicotinamide exacerbates hypoxemia in ventilator-induced lung injury independent of neutrophil infiltration.
Nicotinamide exacerbates hypoxemia in ventilator-induced lung injury independent of neutrophil infiltration.
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烟酰胺加剧了呼吸机诱导的肺损伤的低氧血症，独立于中性粒细胞浸润。
DOI：
10.1371/journal.pone.0123460
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Shimada K
中科院分区：
文献类型：
--
作者：
Jones HD;Yoo J;Crother TR;Kyme P;Ben-Shlomo A;Khalafi R;Tseng CW;Parks WC;Arditi M;Liu GY;Shimada K
呼吸机诱导的肺损伤是一种急性肺损伤，发生在接受机械通气的危重患者中，死亡率很高。烟酰胺磷酸核糖基转移酶是一种在呼吸机诱导的肺损伤中高度上调的酶，当外源性给予时会加重损伤。烟酰胺（维生素B3）直接抑制烟酰胺磷酸核糖基转移酶激活的下游途径，并在其他急性肺损伤模型中具有保护作用。我们给接受高潮气量机械通气的小鼠腹腔注射烟酰胺，以研究烟酰胺对呼吸机诱导的肺损伤的影响。损伤的测量包括氧饱和度和支气管肺泡灌洗液中性粒细胞计数、蛋白质和细胞因子水平。我们还测量了烟酰胺磷酸核糖基转移酶及其下游效应子Sirt 1和Cebpa、Cebpb、Cebpe的表达。我们评估了烟酰胺对呼吸机诱导的肺损伤过程中一氧化氮产生的影响。我们还研究了C/EBPε缺陷小鼠呼吸机诱导的肺损伤的影响。烟酰胺治疗显著抑制中性粒细胞浸润到肺呼吸机诱导的肺损伤，但不影响蛋白质渗漏或细胞因子的产生。令人惊讶的是，用烟酰胺治疗的小鼠在机械通气期间发展出显著更差的低氧血症。这种效应与一氧化氮产生的增加或烟酰胺磷酸核糖转移酶、Sirt 1或Cebpa和Cebpb表达的改变无关。Cebpe mRNA水平在烟酰胺治疗或机械通气下均降低，但缺乏C/EBPε的小鼠与野生型小鼠发生相同程度的低氧血症和呼吸机诱导的肺损伤。VILI期间的烟酰胺治疗可抑制肺中性粒细胞浸润，这与强抗炎作用一致，但矛盾的是，也会导致严重低氧血症的发生。这些结果表明，肺嗜酸性粒细胞与呼吸机诱导的肺损伤中的低氧血症无关，而烟酰胺加重VILI期间的低氧血症。
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. 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. 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. 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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