TY - JOUR
T1 - Circulating cell death biomarker TRAIL is associated with increased organ dysfunction in sepsis
AU - Schenck, Edward J.
AU - Ma, Kevin C.
AU - Price, David R.
AU - Nicholson, Thomas
AU - Oromendia, Clara
AU - Gentzler, Eliza Rose
AU - Sanchez, Elizabeth
AU - Baron, Rebecca M.
AU - Fredenburgh, Laura E.
AU - Huh, Jin Won
AU - Siempos, Ilias I.
AU - Choi, Augustine M.K.
N1 - Publisher Copyright:
© 2019 American Society for Clinical Investigation.
PY - 2019
Y1 - 2019
N2 - BACKGROUND. In sepsis, there may be dysregulation in programed cell death pathways, typified by apoptosis and necroptosis. Programmed cell death pathways may contribute to variability in the immune response. TRAIL is a potent inducer of apoptosis. Receptor-interacting serine/threonine protein kinase-3 (RIPK3) is integral to the execution of necroptosis. We explored whether plasma TRAIL levels were associated with in-hospital mortality, organ dysfunction, and septic shock. We also explored the relationship between TRAIL and RIPK3. METHODS. We performed an observational study of critically ill adults admitted to intensive care units at 3 academic medical centers across 2 continents, using 1 as derivation and the other 2 as validation cohorts. Levels of TRAIL were measured in the plasma of 570 subjects by ELISA. RESULTS. In all cohorts, lower (<28.5 pg/ml) versus higher levels of TRAIL were associated with increased organ dysfunction (P ≤ 0.002) and septic shock (P ≤ 0.004). Lower TRAIL levels were associated with in-hospital mortality in 2 of 3 cohorts (Weill Cornell-Biobank of Critical Illness, P = 0.012; Brigham and Women's Hospital Registry of Critical Illness, P = 0.011; Asan Medical Center, P = 0.369). Lower TRAIL was also associated with increased RIPK3 (P ≤ 0.001). CONCLUSION. Lower levels of TRAIL were associated with septic shock and organ dysfunction in 3 independent ICU cohorts. TRAIL was inversely associated with RIPK3 in all cohorts.
AB - BACKGROUND. In sepsis, there may be dysregulation in programed cell death pathways, typified by apoptosis and necroptosis. Programmed cell death pathways may contribute to variability in the immune response. TRAIL is a potent inducer of apoptosis. Receptor-interacting serine/threonine protein kinase-3 (RIPK3) is integral to the execution of necroptosis. We explored whether plasma TRAIL levels were associated with in-hospital mortality, organ dysfunction, and septic shock. We also explored the relationship between TRAIL and RIPK3. METHODS. We performed an observational study of critically ill adults admitted to intensive care units at 3 academic medical centers across 2 continents, using 1 as derivation and the other 2 as validation cohorts. Levels of TRAIL were measured in the plasma of 570 subjects by ELISA. RESULTS. In all cohorts, lower (<28.5 pg/ml) versus higher levels of TRAIL were associated with increased organ dysfunction (P ≤ 0.002) and septic shock (P ≤ 0.004). Lower TRAIL levels were associated with in-hospital mortality in 2 of 3 cohorts (Weill Cornell-Biobank of Critical Illness, P = 0.012; Brigham and Women's Hospital Registry of Critical Illness, P = 0.011; Asan Medical Center, P = 0.369). Lower TRAIL was also associated with increased RIPK3 (P ≤ 0.001). CONCLUSION. Lower levels of TRAIL were associated with septic shock and organ dysfunction in 3 independent ICU cohorts. TRAIL was inversely associated with RIPK3 in all cohorts.
UR - http://www.scopus.com/inward/record.url?scp=85070660676&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070660676&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.127143
DO - 10.1172/jci.insight.127143
M3 - Article
C2 - 31045578
AN - SCOPUS:85070660676
SN - 2379-3708
VL - 4
JO - JCI insight
JF - JCI insight
IS - 9
M1 - e127143
ER -