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