• Shashaty Michael G S MGS 0000-0002-8766-3418 Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, , John P Reilly, Hilary E Faust, Caitlin M Forker, Ittner Caroline A G CAG Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, 5039 W Gates Building, 3600 Spruce Street, Peggy X Zhang, Meghan J Hotz, David Fitzgerald, Wei Yang, Brian J Anderson, Daniel N Holena, Paul N Lanken, Jason D Christie, Nuala J Meyer, and Nilam S Mangalmurti.
• Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, 5039 W Gates Building, 3600 Spruce Street, Philadelphia, PA, 19104, USA. shashatm@pennmedicine.upenn.edu.
• Crit Care. 2019 Jun 28; 23 (1): 235.

BackgroundNecroptosis, a form of programmed cell death mediated by receptor interacting serine/threonine-protein kinase-3 (RIPK3), is implicated in murine models of acute respiratory distress syndrome (ARDS). We hypothesized that plasma RIPK3 concentrations in sepsis and trauma would be associated with ARDS development and that plasma RIPK3 would reflect changes in lung tissue RIPK3 in a murine model of systemic inflammation.MethodsWe utilized prospective cohort studies of critically ill sepsis (n = 120) and trauma (n = 180) patients and measured plasma RIPK3 at presentation and 48 h. Patients were followed for 6 days for ARDS by the Berlin definition. We used multivariable logistic regression to determine the association of plasma RIPK3 with ARDS in each cohort, adjusting for confounders. In mice, we determined whether plasma and lung tissue RIPK3 levels rise concomitantly 4 h after injection with lipopolysaccharide and ZVAD-FMK, an apoptosis inhibitor.ResultsThe change in plasma RIPK3 from presentation to 48 h (ΔRIPK3) was associated with ARDS in sepsis (OR 1.30, 95% CI 1.03-1.63, per ½ standard deviation) and trauma (OR 1.79, 95% CI 1.33-2.40). This association was not evident for presentation RIPK3 levels. Secondary analyses showed similar findings for the association of ΔRIPK3 with acute kidney injury and 30-day mortality. Mice injected with lipopolysaccharide and ZVAD-FMK had significantly higher plasma (p < 0.001) and lung (p = 0.005) RIPK3 than control mice.ConclusionsThe change in plasma RIPK3 from presentation to 48 h in both sepsis and trauma patients is independently associated with ARDS, and plasma RIPK3 may reflect RIPK3 activity in lung tissue.

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