Plasma based targeted metabolomic analysis reveals alterations of phosphatidylcholines and oxidative stress markers in guinea pig model of allergic asthma

Kertys, Martin; Grendár, Marian; Kosutova, Petra; Mokrá, Daniela; Mokrý, Juraj

doi:10.1016/j.bbadis.2019.165572

Cited by 22 publications

(18 citation statements)

References 67 publications

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“…Levels of secreted phospholipases A 2 (sPLA 2 ) have been found to be increased in the lungs and bronchoalveolar lavage fluid (BALF) of asthmatics following allergen challenge [ 24 , 35 ]. Moreover, analysis of the plasma metabolome discovered increased activity of sPLA 2 in the lungs of guinea pigs in eosinophilic inflammation, while the levels of its substrate phosphatidylcholine were found to be decreased [ 36 ].…”

Section: Phospholipases Play a Key Role In Allergiesmentioning

confidence: 99%

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

Knuplez

Sturm

Marsche

2021

IJMS

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Eosinophils are important effector cells involved in allergic inflammation. When stimulated, eosinophils release a variety of mediators initiating, propagating, and maintaining local inflammation. Both, the activity and concentration of secreted and cytosolic phospholipases (PLAs) are increased in allergic inflammation, promoting the cleavage of phospholipids and thus the production of reactive lipid mediators. Eosinophils express high levels of secreted phospholipase A2 compared to other leukocytes, indicating their direct involvement in the production of lipid mediators during allergic inflammation. On the other side, eosinophils have also been recognized as crucial mediators with regulatory and homeostatic roles in local immunity and repair. Thus, targeting the complex network of lipid mediators offer a unique opportunity to target the over-activation and ‘pro-inflammatory’ phenotype of eosinophils without compromising the survival and functions of tissue-resident and homeostatic eosinophils. Here we provide a comprehensive overview of the critical role of phospholipase-derived lipid mediators in modulating eosinophil activity in health and disease. We focus on lysophospholipids, polyunsaturated fatty acids, and eicosanoids with exciting new perspectives for future drug development.

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Section: Phospholipases Play a Key Role In Allergiesmentioning

confidence: 99%

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

Knuplez

Sturm

Marsche

2021

IJMS

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“…For example, reduced carnitine levels can result in a concomitant decline in mitochondrial free CoA and increased acyl-CoA, which has been linked with progressive emphysema [33,34]. Studies have also shown systemic carnitine reduction during and after paediatric asthma exacerbation [35] and plasma levels were reported to be reduced in a guinea pig model of allergic asthma [36]. Sex-specific differences in circulating carnitine levels have been previously established, with lower constitutive levels in women [37].…”

Section: Discussionmentioning

confidence: 97%

Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study

et al. 2021

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IntroductionAsthma is a heterogeneous disease with poorly defined phenotypes. Severe asthmatics often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication.MethodsBaseline urine was collected prospectively from healthy participants (n=100), mild-to-moderate asthmatics (n=87) and severe asthmatics (n=418) in the cross-sectional U-BIOPRED cohort; 12–18-month longitudinal samples were collected from severe asthmatics (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods.ResultsNinety metabolites were identified, with 40 significantly altered (p<0.05, FDR<0.05) in severe asthma and 23 by OCS use. Multivariate modelling showed that observed metabotypes in healthy participants and mild-to-moderate asthmatics differed significantly from severe asthmatics (p=2.6×10−20), OCS-treated asthmatics differed significantly from non-treated (p=9.5×10−4), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings.ConclusionsThis is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the necessity to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.

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“…Furthermore, norleucine, isoleucine, betaine, and methionine found in this study have never been previously found related to asthma. However, carnitine expression in asthma is controversial, some studies showing high carnitine levels in asthma patients [58][59][60], but others showing decreased plasma carnitine levels in asthma [61,62].…”

Section: Discussionmentioning

confidence: 99%

Effect of You-Gui-Wan on House Dust Mite-Induced Mouse Allergic Asthma via Regulating Amino Acid Metabolic Disorder and Gut Dysbiosis

Hsu

Lin

et al. 2021

Biomolecules

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Chinese herbal remedies have long been used for enhancing immunity and treating asthma. However, the evidence-based efficacy remains to be supported. This study aimed to explore the potential bio-signatures in allergic asthma and the effect of You-Gui-Wan (YGW), a traditional Chinese herbal prescription, on dust mite-induced mouse allergic asthma. Extract of Dermatophagoides pteronyssinus (Der p), a dust mite, was intratracheally administered to induce allergic asthma in mice. Serum metabolomic and 16S rRNA-based microbiome profiling were used to analyze untargeted metabolites with levels significantly changed and gut microbiota composition, respectively. Results indicated that 10 metabolites (acetylcarnitine, carnitine, hypoxanthine, tryptophan, phenylalanine, norleucine, isoleucine, betaine, methionine, and valine), mainly associated with branched-chain amino acid (BCAA) metabolism, aromatic amino acid (AAA) biosynthesis, and phenylalanine metabolism were markedly elevated after Der p treatment. YGW administration reversed the levels for 7 of the 10 identified metabolites, chiefly affecting BCAA metabolism. On 16S DNA sequencing, disordered Der p-induced gut microbiota was significantly alleviated by YGW. Multiple correlation analysis showed a good correlation between gut microbiota composition and levels of selected metabolites. Our study showed YGW administration effectively alleviated BCAA metabolic disorder and improved gut dysbiosis. This study provides support for YGW administration with benefits for allergic asthma.

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Plasma based targeted metabolomic analysis reveals alterations of phosphatidylcholines and oxidative stress markers in guinea pig model of allergic asthma

Cited by 22 publications

References 67 publications

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study

Effect of You-Gui-Wan on House Dust Mite-Induced Mouse Allergic Asthma via Regulating Amino Acid Metabolic Disorder and Gut Dysbiosis

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