Metabolome and lipidome derangements during a severe mast cell activation event in a patient with indolent systemic mastocytosis.
Adult
Amine Oxidase (Copper-Containing)
/ metabolism
Cell Degranulation
Histamine
/ metabolism
Humans
Immunomodulation
Lipidomics
Lysophosphatidylcholines
/ metabolism
Male
Mast Cells
/ immunology
Mastocytosis, Systemic
/ metabolism
Metabolome
Nausea
Nitric Oxide Synthase Type III
/ metabolism
Phosphoric Diester Hydrolases
/ metabolism
Signal Transduction
Vomiting
Histamine
citrulline
diamine oxidase
lysophosphatidic acid
lysophosphatidylcholine
mast cell activation syndrome
mastocytosis
ornithine
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
27
10
2020
revised:
02
03
2021
accepted:
30
03
2021
pubmed:
18
4
2021
medline:
22
12
2021
entrez:
17
4
2021
Statut:
ppublish
Résumé
The number of mast cells in various organs is elevated manifold in individuals with systemic mastocytosis. Degranulation can lead to life-threatening symptomatology. No data about the alterations of the metabolome and lipidome during an attack have been published. Our aim was to analyze changes in metabolomics and lipidomics during the acute phase of a severe mast cell activation event. A total of 43 metabolites and 11 lipid classes comprising 200 subvariants from multiple plasma samples in duplicate, covering 72 hours of a severe mast cell activation attack with nausea and vomiting, were compared with 2 baseline samples by using quantitative liquid chromatography-mass spectrometry. A strong enterocyte dysfunction reflected in an almost 20-fold reduction in the functional small bowel length was extrapolated from strongly reduced ornithine and citrulline concentrations and was very likely secondary to severe endothelial cell dysfunction with hypoperfusion and extensive vascular leakage. Highly increased histamine and lactate concentrations accompanied the peak in clinical symptoms. Elevated asymmetric and symmetric dimethylarginine levels combined with reduced arginine levels compromised endothelial nitric oxide synthase activity and nitric oxide signaling. Specific and extensive depletion of many lysophosphatidylcholine variants indicates localized autotaxin activation and lysophosphatidic acid release. A strong correlation of clinical parameters with histamine concentrations and symptom reduction after 100-fold elevated plasma diamine oxidase concentrations implies that histamine is the key driver of the acute phase. Rapid elimination of elevated histamine concentrations through use of recombinant human diamine oxidase, supplementation of lysophosphatidylcholine for immunomodulation, inhibition of autotaxin activity, and/or blockade of lysophosphatidic acid receptors might represent new treatment options for life-threatening mast cell activation events.
Sections du résumé
BACKGROUND
The number of mast cells in various organs is elevated manifold in individuals with systemic mastocytosis. Degranulation can lead to life-threatening symptomatology. No data about the alterations of the metabolome and lipidome during an attack have been published.
OBJECTIVE
Our aim was to analyze changes in metabolomics and lipidomics during the acute phase of a severe mast cell activation event.
METHODS
A total of 43 metabolites and 11 lipid classes comprising 200 subvariants from multiple plasma samples in duplicate, covering 72 hours of a severe mast cell activation attack with nausea and vomiting, were compared with 2 baseline samples by using quantitative liquid chromatography-mass spectrometry.
RESULTS
A strong enterocyte dysfunction reflected in an almost 20-fold reduction in the functional small bowel length was extrapolated from strongly reduced ornithine and citrulline concentrations and was very likely secondary to severe endothelial cell dysfunction with hypoperfusion and extensive vascular leakage. Highly increased histamine and lactate concentrations accompanied the peak in clinical symptoms. Elevated asymmetric and symmetric dimethylarginine levels combined with reduced arginine levels compromised endothelial nitric oxide synthase activity and nitric oxide signaling. Specific and extensive depletion of many lysophosphatidylcholine variants indicates localized autotaxin activation and lysophosphatidic acid release. A strong correlation of clinical parameters with histamine concentrations and symptom reduction after 100-fold elevated plasma diamine oxidase concentrations implies that histamine is the key driver of the acute phase.
CONCLUSIONS
Rapid elimination of elevated histamine concentrations through use of recombinant human diamine oxidase, supplementation of lysophosphatidylcholine for immunomodulation, inhibition of autotaxin activity, and/or blockade of lysophosphatidic acid receptors might represent new treatment options for life-threatening mast cell activation events.
Identifiants
pubmed: 33864889
pii: S0091-6749(21)00607-2
doi: 10.1016/j.jaci.2021.03.043
pii:
doi:
Substances chimiques
Lysophosphatidylcholines
0
Histamine
820484N8I3
Nitric Oxide Synthase Type III
EC 1.14.13.39
Amine Oxidase (Copper-Containing)
EC 1.4.3.21
Phosphoric Diester Hydrolases
EC 3.1.4.-
alkylglycerophosphoethanolamine phosphodiesterase
EC 3.1.4.39
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1533-1544Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.