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Pressure Controlled Ventilation to Induce Acute Lung Injury in Mice
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Pressure Controlled Ventilation to Induce Acute Lung Injury in Mice

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RIPK3 mediates pathogenesis of experimental ventilator-induced lung injury

Ilias I Siempos1,2, Kevin C Ma1, Mitsuru Imamura1

  • 1Department of Medicine, Division of Pulmonary and Critical Care Medicine, New York-Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medicine (WCM), New York, New York, USA.

JCI Insight
|May 4, 2018
PubMed

Insights

Mechanical ventilation can cause lung injury (VILI). This study found that RIPK3, a cell death regulator, and impaired fatty acid oxidation contribute to VILI, suggesting a new therapeutic target for ventilator-induced lung injury.

Area of Science:

  • Critical Care Medicine
  • Pulmonary Medicine
  • Cellular Biology

Background:

  • Mechanical ventilation (MV) can lead to ventilator-induced lung injury (VILI), a significant cause of morbidity and mortality.
  • VILI involves necrotic cell death, but the role of specific programmed necrotic pathways like necroptosis is unclear.
  • Necroptosis is regulated by receptor-interacting protein-3 kinase (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL).

Purpose of the Study:

  • To investigate the role of necroptosis, specifically RIPK3 and MLKL, in the pathogenesis of VILI.
  • To explore the association between VILI, necroptosis, and fatty acid oxidation (FAO).

Main Methods:

  • Measured plasma levels of RIPK3 and MLKL in human intensive care unit (ICU) cohorts with and without MV.
  • Utilized RIPK3-deficient and MLKL-deficient mouse models to assess VILI development.
  • Assessed fatty acid oxidation (FAO) in both human and mouse models of VILI.

Main Results:

  • Plasma RIPK3 levels were elevated in patients requiring MV, indicating a potential link to VILI.
  • RIPK3 deficiency, but not MLKL deficiency, significantly reduced VILI severity in mice.
  • VILI was associated with impaired FAO in both humans and mice, an effect blunted by RIPK3 deficiency.

Conclusions:

  • RIPK3 plays a critical role in mediating VILI pathogenesis.
  • Impaired FAO is linked to VILI, and this association is dependent on RIPK3.
  • Targeting RIPK3 and restoring FAO may offer novel therapeutic strategies for VILI.
Keywords:
Fatty acid oxidationPulmonology

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