Angiopoietin 2 Is Associated with Vascular Necroptosis Induction in Coronavirus Disease 2019 Acute Respiratory Distress Syndrome

Price, David R.; Benedetti, Elisa; Hoffman, Katherine L.; Gomez-Escobar, Luis; Alvarez-Mulett, Sergio; Capili, Allyson; Sarwath, Hina; Parkhurst, Christopher N.; LaFond, Elyse; Weidman, Karissa; Ravishankar, Arjun; Cheong, Jin-Gyu; Batra, Richa; Büyüközkan, Mustafa; Chetnik, Kelsey; Easthausen, Imaani; Schenck, Edward J.; Racanelli, Alexandra C.; Reed, Hasina Outtz; Laurence, Jeffrey; Josefowicz, Steven Z.; Lief, Lindsay; Choi, Mary E.; Schmidt, Frank; Choi, Augustine M.K.; Krumsiek, Jan; Rafii, Shahin

doi:10.1016/j.ajpath.2022.04.002

Cited by 20 publications

(15 citation statements)

References 63 publications

(46 reference statements)

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“…(4) Metabolomics, lipidomics, and proteomics platforms have limits in terms of the coverage of measured molecules, creating the potential for missed associations. For example, our measurement panel did not contain sphingosine-1 phosphate receptor (S1PR), nitric oxide (NO), and nitric oxide synthases (eNOS, iNOS) from Fig 3 ; angiopoietin 2 (ANGPT2), which has been associated with COVID-19 ARDS-linked vascular necroptosis [ 91 ]; and proinflammatory lipid groups like prostaglandins [ 92 ]. Improvements in measurement technology as well as the integration of data from different platforms will help us generate a more complete picture of ARDS-associated molecular changes in the future.…”

Section: Discussionmentioning

confidence: 99%

Multi-omic comparative analysis of COVID-19 and bacterial sepsis-induced ARDS

Batra

Whalen²,

Alvarez-Mulett³

et al. 2022

PLoS Pathog

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Background Acute respiratory distress syndrome (ARDS), a life-threatening condition characterized by hypoxemia and poor lung compliance, is associated with high mortality. ARDS induced by COVID-19 has similar clinical presentations and pathological manifestations as non-COVID-19 ARDS. However, COVID-19 ARDS is associated with a more protracted inflammatory respiratory failure compared to traditional ARDS. Therefore, a comprehensive molecular comparison of ARDS of different etiologies groups may pave the way for more specific clinical interventions. Methods and findings In this study, we compared COVID-19 ARDS (n = 43) and bacterial sepsis-induced (non-COVID-19) ARDS (n = 24) using multi-omic plasma profiles covering 663 metabolites, 1,051 lipids, and 266 proteins. To address both between- and within- ARDS group variabilities we followed two approaches. First, we identified 706 molecules differently abundant between the two ARDS etiologies, revealing more than 40 biological processes differently regulated between the two groups. From these processes, we assembled a cascade of therapeutically relevant pathways downstream of sphingosine metabolism. The analysis suggests a possible overactivation of arginine metabolism involved in long-term sequelae of ARDS and highlights the potential of JAK inhibitors to improve outcomes in bacterial sepsis-induced ARDS. The second part of our study involved the comparison of the two ARDS groups with respect to clinical manifestations. Using a data-driven multi-omic network, we identified signatures of acute kidney injury (AKI) and thrombocytosis within each ARDS group. The AKI-associated network implicated mitochondrial dysregulation which might lead to post-ARDS renal-sequalae. The thrombocytosis-associated network hinted at a synergy between prothrombotic processes, namely IL-17, MAPK, TNF signaling pathways, and cell adhesion molecules. Thus, we speculate that combination therapy targeting two or more of these processes may ameliorate thrombocytosis-mediated hypercoagulation. Conclusion We present a first comprehensive molecular characterization of differences between two ARDS etiologies–COVID-19 and bacterial sepsis. Further investigation into the identified pathways will lead to a better understanding of the pathophysiological processes, potentially enabling novel therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Multi-omic comparative analysis of COVID-19 and bacterial sepsis-induced ARDS

Batra

Whalen²,

Alvarez-Mulett³

et al. 2022

PLoS Pathog

Self Cite

View full text Add to dashboard Cite

show abstract

“…(4) Metabolomics, lipidomics, and proteomics platforms have limits in terms of the coverage of measured molecules, creating the potential for missed associations. For example, our measurement panel did not contain sphingosine-1 phosphate receptor (S1PR), nitric oxide (NO), and nitric oxide synthases (eNOS, iNOS) from Figure 3, angiopoietin 2 (ANGPT2), which has been associated with COVID-19 ARDS-linked vascular necroptosis [92], and proinflammatory lipid groups like prostaglandins [93]. Improvements in measurement technology as well as the integration of data from different platforms will help us generate a more complete picture of ARDS -associated molecular changes in the future.…”

Section: Discussionmentioning

confidence: 99%

Multi-omic comparative analysis of COVID-19 and bacterial sepsis-induced ARDS

Batra

Whalen

Alvarez-Mulett

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

BackgroundAcute respiratory distress syndrome (ARDS), a life-threatening condition characterized by hypoxemia and poor lung compliance, is associated with high mortality. ARDS induced by COVID-19 has similar clinical presentations and pathological manifestations as non-COVID-19 ARDS. However, COVID-19 ARDS is associated with a more protracted inflammatory respiratory failure compared to traditional ARDS. Therefore, a comprehensive molecular comparison of ARDS of different etiologies groups may pave the way for more specific clinical interventions.Methods and FindingsIn this study, we compared COVID-19 ARDS (n=43) and bacterial sepsis-induced (non-COVID-19) ARDS (n=24) using multi-omic plasma profiles covering 663 metabolites, 1,051 lipids, and 266 proteins. To address both between- and within-ARDS group variabilities we followed two approaches. First, we identified 706 molecules differently abundant between the two ARDS etiologies, revealing more than 40 biological processes differently regulated between the two groups. From these processes, we assembled a cascade of therapeutically relevant pathways downstream of sphingosine metabolism. The analysis suggests a possible overactivation of arginine metabolism involved in long-term sequelae of ARDS and highlights the potential of JAK inhibitors to improve outcomes in bacterial sepsis-induced ARDS. The second part of our study involved the comparison of the two ARDS groups with respect to clinical manifestations. Using a data-driven multi-omic network, we identified signatures of acute kidney injury (AKI) and thrombocytosis within each ARDS group. The AKI-associated network implicated mitochondrial dysregulation which might lead to post-ARDS renal-sequalae. The thrombocytosis-associated network hinted at a synergy between prothrombotic processes, namely IL-17, MAPK, TNF signaling pathways, and cell adhesion molecules. Thus, we speculate that combination therapy targeting two or more of these processes may ameliorate thrombocytosis-mediated hypercoagulation.ConclusionWe present a first comprehensive molecular characterization of differences between two ARDS etiologies – COVID-19 and bacterial sepsis. Further investigation into the identified pathways will lead to a better understanding of the pathophysiological processes, potentially enabling novel therapeutic interventions.

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“…Our study derived a 22-protein vascular injury signature based on blood proteins' association with both mortality and platelet level and showed that this signature correlated with clinical (eg, mortality and recovery) as well as pathophysiological [eg, platelets, angiopoietin 2 (ANGPT2), and necrotic vascular cell death] readouts throughout the time course of coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS). 1 Notably, the data demonstrated that this association held even when non–COVID-19 ARDS subjects were included in the analysis.…”

mentioning

confidence: 87%

“…Melegari et al suggest that serial measurements of ANGPT2 separated by 3 days are a more feasible prognostic biomarker for COVID-19 than the baseline measurement of the 22-protein signature derived in the mentioned article. 1 After a multivariable adjustment, a twofold increase in ANGPT2 over 3 days accurately predicted mortality in a mixed disease severity cohort of COVID-19 subjects. 2 These findings fit nicely with the robust literature linking ANGPT2 and prognosis in sepsis/acute lung injury: ANGPT2 has been linked to prognosis in sepsis 3 , 4 and ARDS, 5 including a large meta-analysis.…”

mentioning

confidence: 95%