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RIPK3 mediates pathogenesis of experimental ventilator-induced lung injury
Ilias I. Siempos, … , Kiichi Nakahira, Augustine M.K. Choi
Ilias I. Siempos, … , Kiichi Nakahira, Augustine M.K. Choi
Published May 3, 2018
Citation Information: JCI Insight. 2018;3(9):e97102. https://doi.org/10.1172/jci.insight.97102.
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Research Article Pulmonology

RIPK3 mediates pathogenesis of experimental ventilator-induced lung injury

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Abstract

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.

Authors

Ilias I. Siempos, Kevin C. Ma, Mitsuru Imamura, Rebecca M. Baron, Laura E. Fredenburgh, Jin-Won Huh, Jong-Seok Moon, Eli J. Finkelsztein, Daniel S. Jones, Michael Torres Lizardi, Edward J. Schenck, Stefan W. Ryter, Kiichi Nakahira, Augustine M.K. Choi

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Figure 1

Elevation of plasma RIPK3, but not RIPK1 or MLKL, levels in mechanically ventilated patients in the intensive care unit.

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Elevation of plasma RIPK3, but not RIPK1 or MLKL, levels in mechanically...
(A) RIPK3 levels were plotted for patients with versus without mechanical ventilation (MV) in the Weill Cornell Medicine (WCM) cohort (n = 155). (B and C) For the WCM cohort, plasma RIPK1 levels were (B) plotted for patients with versus without MV and (C) correlated with plasma RIPK3 levels (n = 40). (D and E) For the WCM cohort, plasma MLKL levels were (D) plotted for patients with versus without MV and (E) correlated with plasma RIPK3 levels (n = 111). Red bars represent mean ± SEM. Statistical significance was calculated using Mann-Whitney U (A, B, and D) and Pearson’s correlation (C and E) tests.

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