RIPK3 mediates pathogenesis of experimental ventilator-induced lung injury
RIPK3 mediates pathogenesis of experimental ventilator-induced lung injury
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DOI：
10.1172/jci.insight.97102
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发表时间：
2018-05-03
期刊：
影响因子：
8
通讯作者：
Choi, Augustine M. K.
中科院分区：
文献类型：
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作者：
Siempos, Ilias I.;Ma, Kevin C.;Choi, Augustine M. K.
对于需要呼吸机支持的患者，机械通气 (MV) 可能会诱发急性肺损伤（呼吸机诱发性肺损伤 [VILI]）。 VILI 与患有或不患有急性呼吸窘迫综合征的机械通气患者的高发病率和死亡率相关。在细胞水平上，VILI 诱导坏死性细胞死亡。然而，坏死性凋亡是一种由受体相互作用蛋白 3 激酶 (RIPK3) 和混合谱系激酶结构域样假激酶 (MLKL) 调节的程序性坏死细胞死亡形式，其对 VILI 发展的贡献尚未被探索。在这里，我们发现，在两个大型重症监护病房队列中，MV 患者（即容易发生 VILI 的患者）的血浆 RIPK3（而非 MLKL）水平高于无 MV 患者（即不太可能发生 VILI 的患者）。在小鼠中，RIPK3 缺陷而非 MLKL 缺陷改善了 VILI。在人类和小鼠中，VILI 与脂肪酸氧化受损 (FAO) 相关，但在小鼠中，在 RIPK3 缺乏的情况下并未观察到这种关联。这些发现表明，FAO 依赖性 RIPK3 介导急性肺损伤的发病机制。
In patients requiring ventilator support, mechanical ventilation (MV) may induce acute lung injury (ventilator-induced lung injury [VILI]). VILI is associated with substantial morbidity and mortality in mechanically ventilated patients with and without acute respiratory distress syndrome. At the cellular level, VILI induces necrotic cell death. However, the contribution of necroptosis, a programmed form of necrotic cell death regulated by receptor-interacting protein-3 kinase (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL), to the development of VILI remains unexplored. Here, we show that plasma levels of RIPK3, but not MLKL, were higher in patients with MV (i.e., those prone to VILI) than in patients without MV (i.e., those less likely to have VILI) in two large intensive care unit cohorts. In mice, RIPK3 deficiency, but not MLKL deficiency, ameliorated VILI. In both humans and mice, VILI was associated with impaired fatty acid oxidation (FAO), but in mice this association was not observed under conditions of RIPK3 deficiency. These findings suggest that FAO-dependent RIPK3 mediates pathogenesis of acute lung injury.