Metabolomic Characterization of Human Model of Liver Rejection Identifies Aberrancies Linked to Cyclooxygenase (COX) and Nitric Oxide Synthase (NOS)

N. Skill, Campbell M. Elliott, Brian Ceballos, Romil Saxena, Robert Pepin, Lisa Bettcher, Matthew Ellensberg, Daniel Raftery, Mary Maluccio, Burcin Ekser, Richard Mangus, Chandrashekhar A. Kubal

Research output: Contribution to journalArticle

Abstract

BACKGROUND Acute liver rejection (ALR), a significant complication of liver transplantation, burdens patients, healthcare payers, and the healthcare providers due to an increase in morbidity, cost, and resources. Despite clinical resolution, ALR is associated with an increased risk of graft loss. A unique protocol of delayed immunosuppression used in our institute provided a model to characterize metabolomic profiles in human ALR. MATERIAL AND METHODS Twenty liver allograft biopsies obtained 48 hours after liver transplantation in the absence of immunosuppression were studied. Hepatic metabolites were quantitated in these biopsies by liquid chromatography and mass spectroscopy (LC/MS). Metabolite profiles were compared among: 1) biopsies with reperfusion injury but no histological evidence of rejection (n=7), 2) biopsies with histological evidence of moderate or severe rejection (n=5), and 3) biopsies with histological evidence of mild rejection (n=8). RESULTS There were 133 metabolites consistently detected by LC/MS and these were prioritized using variable importance to projection (VIP) analysis, comparing moderate or severe rejection vs. no rejection or mild rejection using partial least squares discriminant statistical analysis (PLS-DA). Twenty metabolites were identified as progressively different. Further PLS-DA using these metabolites identified 3 metabolites (linoleic acid, γ-linolenic acid, and citrulline) which are associated with either cyclooxygenase or nitric oxide synthase functionality. CONCLUSIONS Hepatic metabolic aberrancies associated with cyclooxygenase and nitric oxide synthase function occur contemporaneous with ALR. Additional studies are required to better characterize the role of these metabolic pathways to enhance utility of the metabolomics approach in diagnosis and outcomes of ALR.

Original languageEnglish (US)
Pages (from-to)341-349
Number of pages9
JournalAnnals of transplantation
Volume24
DOIs
StatePublished - Jun 11 2019

Fingerprint

Metabolomics
Prostaglandin-Endoperoxide Synthases
Nitric Oxide Synthase
Liver
Biopsy
Discriminant Analysis
Least-Squares Analysis
Liquid Chromatography
Liver Transplantation
Immunosuppression
Mass Spectrometry
Citrulline
alpha-Linolenic Acid
Metabolic Networks and Pathways
Reperfusion Injury
Health Personnel
Allografts
Morbidity
Delivery of Health Care
Transplants

ASJC Scopus subject areas

  • Transplantation

Cite this

Metabolomic Characterization of Human Model of Liver Rejection Identifies Aberrancies Linked to Cyclooxygenase (COX) and Nitric Oxide Synthase (NOS). / Skill, N.; Elliott, Campbell M.; Ceballos, Brian; Saxena, Romil; Pepin, Robert; Bettcher, Lisa; Ellensberg, Matthew; Raftery, Daniel; Maluccio, Mary; Ekser, Burcin; Mangus, Richard; Kubal, Chandrashekhar A.

In: Annals of transplantation, Vol. 24, 11.06.2019, p. 341-349.

Research output: Contribution to journalArticle

Skill, N. ; Elliott, Campbell M. ; Ceballos, Brian ; Saxena, Romil ; Pepin, Robert ; Bettcher, Lisa ; Ellensberg, Matthew ; Raftery, Daniel ; Maluccio, Mary ; Ekser, Burcin ; Mangus, Richard ; Kubal, Chandrashekhar A. / Metabolomic Characterization of Human Model of Liver Rejection Identifies Aberrancies Linked to Cyclooxygenase (COX) and Nitric Oxide Synthase (NOS). In: Annals of transplantation. 2019 ; Vol. 24. pp. 341-349.
@article{58c563382bbc4eae852dbff20c640c3b,
title = "Metabolomic Characterization of Human Model of Liver Rejection Identifies Aberrancies Linked to Cyclooxygenase (COX) and Nitric Oxide Synthase (NOS)",
abstract = "BACKGROUND Acute liver rejection (ALR), a significant complication of liver transplantation, burdens patients, healthcare payers, and the healthcare providers due to an increase in morbidity, cost, and resources. Despite clinical resolution, ALR is associated with an increased risk of graft loss. A unique protocol of delayed immunosuppression used in our institute provided a model to characterize metabolomic profiles in human ALR. MATERIAL AND METHODS Twenty liver allograft biopsies obtained 48 hours after liver transplantation in the absence of immunosuppression were studied. Hepatic metabolites were quantitated in these biopsies by liquid chromatography and mass spectroscopy (LC/MS). Metabolite profiles were compared among: 1) biopsies with reperfusion injury but no histological evidence of rejection (n=7), 2) biopsies with histological evidence of moderate or severe rejection (n=5), and 3) biopsies with histological evidence of mild rejection (n=8). RESULTS There were 133 metabolites consistently detected by LC/MS and these were prioritized using variable importance to projection (VIP) analysis, comparing moderate or severe rejection vs. no rejection or mild rejection using partial least squares discriminant statistical analysis (PLS-DA). Twenty metabolites were identified as progressively different. Further PLS-DA using these metabolites identified 3 metabolites (linoleic acid, γ-linolenic acid, and citrulline) which are associated with either cyclooxygenase or nitric oxide synthase functionality. CONCLUSIONS Hepatic metabolic aberrancies associated with cyclooxygenase and nitric oxide synthase function occur contemporaneous with ALR. Additional studies are required to better characterize the role of these metabolic pathways to enhance utility of the metabolomics approach in diagnosis and outcomes of ALR.",
author = "N. Skill and Elliott, {Campbell M.} and Brian Ceballos and Romil Saxena and Robert Pepin and Lisa Bettcher and Matthew Ellensberg and Daniel Raftery and Mary Maluccio and Burcin Ekser and Richard Mangus and Kubal, {Chandrashekhar A.}",
year = "2019",
month = "6",
day = "11",
doi = "10.12659/AOT.913800",
language = "English (US)",
volume = "24",
pages = "341--349",
journal = "Annals of Transplantation",
issn = "1425-9524",
publisher = "International Scientific Information, Inc.",

}

TY - JOUR

T1 - Metabolomic Characterization of Human Model of Liver Rejection Identifies Aberrancies Linked to Cyclooxygenase (COX) and Nitric Oxide Synthase (NOS)

AU - Skill, N.

AU - Elliott, Campbell M.

AU - Ceballos, Brian

AU - Saxena, Romil

AU - Pepin, Robert

AU - Bettcher, Lisa

AU - Ellensberg, Matthew

AU - Raftery, Daniel

AU - Maluccio, Mary

AU - Ekser, Burcin

AU - Mangus, Richard

AU - Kubal, Chandrashekhar A.

PY - 2019/6/11

Y1 - 2019/6/11

N2 - BACKGROUND Acute liver rejection (ALR), a significant complication of liver transplantation, burdens patients, healthcare payers, and the healthcare providers due to an increase in morbidity, cost, and resources. Despite clinical resolution, ALR is associated with an increased risk of graft loss. A unique protocol of delayed immunosuppression used in our institute provided a model to characterize metabolomic profiles in human ALR. MATERIAL AND METHODS Twenty liver allograft biopsies obtained 48 hours after liver transplantation in the absence of immunosuppression were studied. Hepatic metabolites were quantitated in these biopsies by liquid chromatography and mass spectroscopy (LC/MS). Metabolite profiles were compared among: 1) biopsies with reperfusion injury but no histological evidence of rejection (n=7), 2) biopsies with histological evidence of moderate or severe rejection (n=5), and 3) biopsies with histological evidence of mild rejection (n=8). RESULTS There were 133 metabolites consistently detected by LC/MS and these were prioritized using variable importance to projection (VIP) analysis, comparing moderate or severe rejection vs. no rejection or mild rejection using partial least squares discriminant statistical analysis (PLS-DA). Twenty metabolites were identified as progressively different. Further PLS-DA using these metabolites identified 3 metabolites (linoleic acid, γ-linolenic acid, and citrulline) which are associated with either cyclooxygenase or nitric oxide synthase functionality. CONCLUSIONS Hepatic metabolic aberrancies associated with cyclooxygenase and nitric oxide synthase function occur contemporaneous with ALR. Additional studies are required to better characterize the role of these metabolic pathways to enhance utility of the metabolomics approach in diagnosis and outcomes of ALR.

AB - BACKGROUND Acute liver rejection (ALR), a significant complication of liver transplantation, burdens patients, healthcare payers, and the healthcare providers due to an increase in morbidity, cost, and resources. Despite clinical resolution, ALR is associated with an increased risk of graft loss. A unique protocol of delayed immunosuppression used in our institute provided a model to characterize metabolomic profiles in human ALR. MATERIAL AND METHODS Twenty liver allograft biopsies obtained 48 hours after liver transplantation in the absence of immunosuppression were studied. Hepatic metabolites were quantitated in these biopsies by liquid chromatography and mass spectroscopy (LC/MS). Metabolite profiles were compared among: 1) biopsies with reperfusion injury but no histological evidence of rejection (n=7), 2) biopsies with histological evidence of moderate or severe rejection (n=5), and 3) biopsies with histological evidence of mild rejection (n=8). RESULTS There were 133 metabolites consistently detected by LC/MS and these were prioritized using variable importance to projection (VIP) analysis, comparing moderate or severe rejection vs. no rejection or mild rejection using partial least squares discriminant statistical analysis (PLS-DA). Twenty metabolites were identified as progressively different. Further PLS-DA using these metabolites identified 3 metabolites (linoleic acid, γ-linolenic acid, and citrulline) which are associated with either cyclooxygenase or nitric oxide synthase functionality. CONCLUSIONS Hepatic metabolic aberrancies associated with cyclooxygenase and nitric oxide synthase function occur contemporaneous with ALR. Additional studies are required to better characterize the role of these metabolic pathways to enhance utility of the metabolomics approach in diagnosis and outcomes of ALR.

UR - http://www.scopus.com/inward/record.url?scp=85067796638&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067796638&partnerID=8YFLogxK

U2 - 10.12659/AOT.913800

DO - 10.12659/AOT.913800

M3 - Article

VL - 24

SP - 341

EP - 349

JO - Annals of Transplantation

JF - Annals of Transplantation

SN - 1425-9524

ER -