TY - JOUR
T1 - Angiopoietin 2 Is Associated with Vascular Necroptosis Induction in Coronavirus Disease 2019 Acute Respiratory Distress Syndrome
AU - Price, David R.
AU - Benedetti, Elisa
AU - Hoffman, Katherine L.
AU - Gomez-Escobar, Luis
AU - Alvarez-Mulett, Sergio
AU - Capili, Allyson
AU - Sarwath, Hina
AU - Parkhurst, Christopher N.
AU - Lafond, Elyse
AU - Weidman, Karissa
AU - Ravishankar, Arjun
AU - Cheong, Jin Gyu
AU - Batra, Richa
AU - Büyüközkan, Mustafa
AU - Chetnik, Kelsey
AU - Easthausen, Imaani
AU - Schenck, Edward J.
AU - Racanelli, Alexandra C.
AU - Outtz Reed, Hasina
AU - Laurence, Jeffrey
AU - Josefowicz, Steven Z.
AU - Lief, Lindsay
AU - Choi, Mary E.
AU - Schmidt, Frank
AU - Borczuk, Alain C.
AU - Choi, Augustine M.K.
AU - Krumsiek, Jan
AU - Rafii, Shahin
N1 - Funding Information:
Supported by the Biomedical Research Program at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation ; the NIH National Institute of Aging award 1U19AG063744 (J.K.); the NIH National Heart, Lung, and Blood Institute grant T32HL134629-01A1 (D.R.P.); and Stony Wold-Herbert Fellowship Fund (United States; D.R.P.).
Publisher Copyright:
© 2022 American Society for Investigative Pathology
PY - 2022/7
Y1 - 2022/7
N2 - Vascular injury is a well-established, disease-modifying factor in acute respiratory distress syndrome (ARDS) pathogenesis. Recently, coronavirus disease 2019 (COVID-19)–induced injury to the vascular compartment has been linked to complement activation, microvascular thrombosis, and dysregulated immune responses. This study sought to assess whether aberrant vascular activation in this prothrombotic context was associated with the induction of necroptotic vascular cell death. To achieve this, proteomic analysis was performed on blood samples from COVID-19 subjects at distinct time points during ARDS pathogenesis (hospitalized at risk, N = 59; ARDS, N = 31; and recovery, N = 12). Assessment of circulating vascular markers in the at-risk cohort revealed a signature of low vascular protein abundance that tracked with low platelet levels and increased mortality. This signature was replicated in the ARDS cohort and correlated with increased plasma angiopoietin 2 levels. COVID-19 ARDS lung autopsy immunostaining confirmed a link between vascular injury (angiopoietin 2) and platelet-rich microthrombi (CD61) and induction of necrotic cell death [phosphorylated mixed lineage kinase domain-like (pMLKL)]. Among recovery subjects, the vascular signature identified patients with poor functional outcomes. Taken together, this vascular injury signature was associated with low platelet levels and increased mortality and can be used to identify ARDS patients most likely to benefit from vascular targeted therapies.
AB - Vascular injury is a well-established, disease-modifying factor in acute respiratory distress syndrome (ARDS) pathogenesis. Recently, coronavirus disease 2019 (COVID-19)–induced injury to the vascular compartment has been linked to complement activation, microvascular thrombosis, and dysregulated immune responses. This study sought to assess whether aberrant vascular activation in this prothrombotic context was associated with the induction of necroptotic vascular cell death. To achieve this, proteomic analysis was performed on blood samples from COVID-19 subjects at distinct time points during ARDS pathogenesis (hospitalized at risk, N = 59; ARDS, N = 31; and recovery, N = 12). Assessment of circulating vascular markers in the at-risk cohort revealed a signature of low vascular protein abundance that tracked with low platelet levels and increased mortality. This signature was replicated in the ARDS cohort and correlated with increased plasma angiopoietin 2 levels. COVID-19 ARDS lung autopsy immunostaining confirmed a link between vascular injury (angiopoietin 2) and platelet-rich microthrombi (CD61) and induction of necrotic cell death [phosphorylated mixed lineage kinase domain-like (pMLKL)]. Among recovery subjects, the vascular signature identified patients with poor functional outcomes. Taken together, this vascular injury signature was associated with low platelet levels and increased mortality and can be used to identify ARDS patients most likely to benefit from vascular targeted therapies.
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U2 - 10.1016/j.ajpath.2022.04.002
DO - 10.1016/j.ajpath.2022.04.002
M3 - Article
C2 - 35469796
AN - SCOPUS:85132786288
VL - 192
SP - 1001
EP - 1015
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 7
ER -