Plasma glycoproteomics reveals sepsis outcomes linked to distinct proteins in common pathways

Ashley De Coux, Yuan Tian, Kristine Y. Deleon-Pennell, Nguyen T. Nguyen, Lisandra E. De Castro Brás, Elizabeth R. Flynn, Presley L. Cannon, Michael E. Griswold, Yu Fang Jin, Michael A. Puskarich, Alan E. Jones, Merry L. Lindsey

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Objective: Sepsis remains a predominant cause of mortality in the ICU, yet strategies to increase survival have proved largely unsuccessful. This study aimed to identify proteins linked to sepsis outcomes using a glycoproteomic approach to target extracellular proteins that trigger downstream pathways and direct patient outcomes. Design: Plasma was obtained from the Lactate Assessment in the Treatment of Early Sepsis cohort. N-linked plasma glycopeptides were quantified by solid-phase extraction coupled with mass spectrometry. Glycopeptides were assigned to proteins using RefSeq (National Center of Biotechnology Information, Bethesda, MD) and visualized in a heat map. Protein differences were validated by immunoblotting, and proteins were mapped for biological processes using Database for Annotation, Visualization and Integrated Discovery (National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD) and for functional pathways using Kyoto Encyclopedia of Genes and Genomes (Kanehisa Laboratories, Kyoto, Japan) databases. Setting: Hospitalized care. Patients: Patients admitted to the emergency department were enrolled in the study when the diagnosis of sepsis was made, within 6 hours of presentation. Interventions: None. Measurements and Main Results: A total of 501 glycopeptides corresponding to 234 proteins were identified. Of these, 66 glycopeptides were unique to the survivor group and corresponded to 54 proteins, 60 were unique to the nonsurvivor group and corresponded to 43 proteins, and 375 were common responses between groups and corresponded to 137 proteins. Immunoblotting showed that nonsurvivors had increased total kininogen; decreased total cathepsin-L1, vascular cell adhesion molecule, periostin, and neutrophil gelatinase-associated lipocalin; and a two-fold decrease in glycosylated clusterin (all p < 0.05). Kyoto Encyclopedia of Genes and Genomes analysis identified six enriched pathways. Interestingly, survivors relied on the extrinsic pathway of the complement and coagulation cascade, whereas nonsurvivors relied on the intrinsic pathway. Conclusion: This study identifies proteins linked to patient outcomes and provides insight into unexplored mechanisms that can be investigated for the identification of novel therapeutic targets.

Original languageEnglish (US)
Pages (from-to)2049-2058
Number of pages10
JournalCritical care medicine
Volume43
Issue number10
DOIs
StatePublished - Oct 1 2015

Fingerprint

Sepsis
Glycopeptides
Proteins
Encyclopedias
Immunoblotting
Survivors
National Institute of Allergy and Infectious Diseases (U.S.)
Neural Cell Adhesion Molecule L1
Genome
Databases
Clusterin
Kininogens
Biological Phenomena
Information Centers
Cathepsins
Vascular Cell Adhesion Molecule-1
Solid Phase Extraction
National Institutes of Health (U.S.)
Biotechnology
Genes

Keywords

  • Blood coagulation factors
  • Complement system proteins
  • Computational biology
  • Glycoproteins
  • Proteomics
  • Sepsis

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

De Coux, A., Tian, Y., Deleon-Pennell, K. Y., Nguyen, N. T., De Castro Brás, L. E., Flynn, E. R., ... Lindsey, M. L. (2015). Plasma glycoproteomics reveals sepsis outcomes linked to distinct proteins in common pathways. Critical care medicine, 43(10), 2049-2058. https://doi.org/10.1097/CCM.0000000000001134

Plasma glycoproteomics reveals sepsis outcomes linked to distinct proteins in common pathways. / De Coux, Ashley; Tian, Yuan; Deleon-Pennell, Kristine Y.; Nguyen, Nguyen T.; De Castro Brás, Lisandra E.; Flynn, Elizabeth R.; Cannon, Presley L.; Griswold, Michael E.; Jin, Yu Fang; Puskarich, Michael A.; Jones, Alan E.; Lindsey, Merry L.

In: Critical care medicine, Vol. 43, No. 10, 01.10.2015, p. 2049-2058.

Research output: Contribution to journalArticle

De Coux, A, Tian, Y, Deleon-Pennell, KY, Nguyen, NT, De Castro Brás, LE, Flynn, ER, Cannon, PL, Griswold, ME, Jin, YF, Puskarich, MA, Jones, AE & Lindsey, ML 2015, 'Plasma glycoproteomics reveals sepsis outcomes linked to distinct proteins in common pathways', Critical care medicine, vol. 43, no. 10, pp. 2049-2058. https://doi.org/10.1097/CCM.0000000000001134
De Coux A, Tian Y, Deleon-Pennell KY, Nguyen NT, De Castro Brás LE, Flynn ER et al. Plasma glycoproteomics reveals sepsis outcomes linked to distinct proteins in common pathways. Critical care medicine. 2015 Oct 1;43(10):2049-2058. https://doi.org/10.1097/CCM.0000000000001134
De Coux, Ashley ; Tian, Yuan ; Deleon-Pennell, Kristine Y. ; Nguyen, Nguyen T. ; De Castro Brás, Lisandra E. ; Flynn, Elizabeth R. ; Cannon, Presley L. ; Griswold, Michael E. ; Jin, Yu Fang ; Puskarich, Michael A. ; Jones, Alan E. ; Lindsey, Merry L. / Plasma glycoproteomics reveals sepsis outcomes linked to distinct proteins in common pathways. In: Critical care medicine. 2015 ; Vol. 43, No. 10. pp. 2049-2058.
@article{628513f12c04476bb6473f285c2a90fa,
title = "Plasma glycoproteomics reveals sepsis outcomes linked to distinct proteins in common pathways",
abstract = "Objective: Sepsis remains a predominant cause of mortality in the ICU, yet strategies to increase survival have proved largely unsuccessful. This study aimed to identify proteins linked to sepsis outcomes using a glycoproteomic approach to target extracellular proteins that trigger downstream pathways and direct patient outcomes. Design: Plasma was obtained from the Lactate Assessment in the Treatment of Early Sepsis cohort. N-linked plasma glycopeptides were quantified by solid-phase extraction coupled with mass spectrometry. Glycopeptides were assigned to proteins using RefSeq (National Center of Biotechnology Information, Bethesda, MD) and visualized in a heat map. Protein differences were validated by immunoblotting, and proteins were mapped for biological processes using Database for Annotation, Visualization and Integrated Discovery (National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD) and for functional pathways using Kyoto Encyclopedia of Genes and Genomes (Kanehisa Laboratories, Kyoto, Japan) databases. Setting: Hospitalized care. Patients: Patients admitted to the emergency department were enrolled in the study when the diagnosis of sepsis was made, within 6 hours of presentation. Interventions: None. Measurements and Main Results: A total of 501 glycopeptides corresponding to 234 proteins were identified. Of these, 66 glycopeptides were unique to the survivor group and corresponded to 54 proteins, 60 were unique to the nonsurvivor group and corresponded to 43 proteins, and 375 were common responses between groups and corresponded to 137 proteins. Immunoblotting showed that nonsurvivors had increased total kininogen; decreased total cathepsin-L1, vascular cell adhesion molecule, periostin, and neutrophil gelatinase-associated lipocalin; and a two-fold decrease in glycosylated clusterin (all p < 0.05). Kyoto Encyclopedia of Genes and Genomes analysis identified six enriched pathways. Interestingly, survivors relied on the extrinsic pathway of the complement and coagulation cascade, whereas nonsurvivors relied on the intrinsic pathway. Conclusion: This study identifies proteins linked to patient outcomes and provides insight into unexplored mechanisms that can be investigated for the identification of novel therapeutic targets.",
keywords = "Blood coagulation factors, Complement system proteins, Computational biology, Glycoproteins, Proteomics, Sepsis",
author = "{De Coux}, Ashley and Yuan Tian and Deleon-Pennell, {Kristine Y.} and Nguyen, {Nguyen T.} and {De Castro Br{\'a}s}, {Lisandra E.} and Flynn, {Elizabeth R.} and Cannon, {Presley L.} and Griswold, {Michael E.} and Jin, {Yu Fang} and Puskarich, {Michael A.} and Jones, {Alan E.} and Lindsey, {Merry L.}",
year = "2015",
month = "10",
day = "1",
doi = "10.1097/CCM.0000000000001134",
language = "English (US)",
volume = "43",
pages = "2049--2058",
journal = "Critical Care Medicine",
issn = "0090-3493",
publisher = "Lippincott Williams and Wilkins",
number = "10",

}

TY - JOUR

T1 - Plasma glycoproteomics reveals sepsis outcomes linked to distinct proteins in common pathways

AU - De Coux, Ashley

AU - Tian, Yuan

AU - Deleon-Pennell, Kristine Y.

AU - Nguyen, Nguyen T.

AU - De Castro Brás, Lisandra E.

AU - Flynn, Elizabeth R.

AU - Cannon, Presley L.

AU - Griswold, Michael E.

AU - Jin, Yu Fang

AU - Puskarich, Michael A.

AU - Jones, Alan E.

AU - Lindsey, Merry L.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - Objective: Sepsis remains a predominant cause of mortality in the ICU, yet strategies to increase survival have proved largely unsuccessful. This study aimed to identify proteins linked to sepsis outcomes using a glycoproteomic approach to target extracellular proteins that trigger downstream pathways and direct patient outcomes. Design: Plasma was obtained from the Lactate Assessment in the Treatment of Early Sepsis cohort. N-linked plasma glycopeptides were quantified by solid-phase extraction coupled with mass spectrometry. Glycopeptides were assigned to proteins using RefSeq (National Center of Biotechnology Information, Bethesda, MD) and visualized in a heat map. Protein differences were validated by immunoblotting, and proteins were mapped for biological processes using Database for Annotation, Visualization and Integrated Discovery (National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD) and for functional pathways using Kyoto Encyclopedia of Genes and Genomes (Kanehisa Laboratories, Kyoto, Japan) databases. Setting: Hospitalized care. Patients: Patients admitted to the emergency department were enrolled in the study when the diagnosis of sepsis was made, within 6 hours of presentation. Interventions: None. Measurements and Main Results: A total of 501 glycopeptides corresponding to 234 proteins were identified. Of these, 66 glycopeptides were unique to the survivor group and corresponded to 54 proteins, 60 were unique to the nonsurvivor group and corresponded to 43 proteins, and 375 were common responses between groups and corresponded to 137 proteins. Immunoblotting showed that nonsurvivors had increased total kininogen; decreased total cathepsin-L1, vascular cell adhesion molecule, periostin, and neutrophil gelatinase-associated lipocalin; and a two-fold decrease in glycosylated clusterin (all p < 0.05). Kyoto Encyclopedia of Genes and Genomes analysis identified six enriched pathways. Interestingly, survivors relied on the extrinsic pathway of the complement and coagulation cascade, whereas nonsurvivors relied on the intrinsic pathway. Conclusion: This study identifies proteins linked to patient outcomes and provides insight into unexplored mechanisms that can be investigated for the identification of novel therapeutic targets.

AB - Objective: Sepsis remains a predominant cause of mortality in the ICU, yet strategies to increase survival have proved largely unsuccessful. This study aimed to identify proteins linked to sepsis outcomes using a glycoproteomic approach to target extracellular proteins that trigger downstream pathways and direct patient outcomes. Design: Plasma was obtained from the Lactate Assessment in the Treatment of Early Sepsis cohort. N-linked plasma glycopeptides were quantified by solid-phase extraction coupled with mass spectrometry. Glycopeptides were assigned to proteins using RefSeq (National Center of Biotechnology Information, Bethesda, MD) and visualized in a heat map. Protein differences were validated by immunoblotting, and proteins were mapped for biological processes using Database for Annotation, Visualization and Integrated Discovery (National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, MD) and for functional pathways using Kyoto Encyclopedia of Genes and Genomes (Kanehisa Laboratories, Kyoto, Japan) databases. Setting: Hospitalized care. Patients: Patients admitted to the emergency department were enrolled in the study when the diagnosis of sepsis was made, within 6 hours of presentation. Interventions: None. Measurements and Main Results: A total of 501 glycopeptides corresponding to 234 proteins were identified. Of these, 66 glycopeptides were unique to the survivor group and corresponded to 54 proteins, 60 were unique to the nonsurvivor group and corresponded to 43 proteins, and 375 were common responses between groups and corresponded to 137 proteins. Immunoblotting showed that nonsurvivors had increased total kininogen; decreased total cathepsin-L1, vascular cell adhesion molecule, periostin, and neutrophil gelatinase-associated lipocalin; and a two-fold decrease in glycosylated clusterin (all p < 0.05). Kyoto Encyclopedia of Genes and Genomes analysis identified six enriched pathways. Interestingly, survivors relied on the extrinsic pathway of the complement and coagulation cascade, whereas nonsurvivors relied on the intrinsic pathway. Conclusion: This study identifies proteins linked to patient outcomes and provides insight into unexplored mechanisms that can be investigated for the identification of novel therapeutic targets.

KW - Blood coagulation factors

KW - Complement system proteins

KW - Computational biology

KW - Glycoproteins

KW - Proteomics

KW - Sepsis

UR - http://www.scopus.com/inward/record.url?scp=84941926243&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941926243&partnerID=8YFLogxK

U2 - 10.1097/CCM.0000000000001134

DO - 10.1097/CCM.0000000000001134

M3 - Article

C2 - 26086942

AN - SCOPUS:84941926243

VL - 43

SP - 2049

EP - 2058

JO - Critical Care Medicine

JF - Critical Care Medicine

SN - 0090-3493

IS - 10

ER -