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Arginine metabolic control of airway inflammation.

ABSTRACT: Inducible nitric oxide synthase (iNOS) and arginase-2 (ARG2) share a common substrate, arginine. Higher expression of iNOS and exhaled NO are linked to airway inflammation in patients. iNOS deletion in animal models suggests that eosinophilic inflammation is regulated by arginine metabolism. Moreover, ARG2 is a regulator of Th2 response, as shown by the development of severe eosinophilic inflammation in ARG2-/- mice. However, potential synergistic roles of iNOS and ARG2 in asthma have not been explored. Here, we hypothesized that arginine metabolic fate via iNOS and ARG2 may govern airway inflammation. In an asthma cohort, ARG2 variant genotypes were associated with arginase activity. ARG2 variants with lower arginase activity, combined with levels of exhaled NO, identified a severe asthma phenotype. Airway inflammation was present in WT, ARG2-/-, iNOS-/-, and ARG2-/-/iNOS-/- mice but was greatest in ARG2-/-. Eosinophilic and neutrophilic infiltration in the ARG2-/- mice was abrogated in ARG2-/-/iNOS-/- animals. Similarly, angiogenic airway remodeling was greatest in ARG2-/- mice. Cytokines driving inflammation and remodeling were highest in lungs of asthmatic ARG2-/- mice and lowest in the iNOS-/-. ARG2 metabolism of arginine suppresses inflammation, while iNOS metabolism promotes airway inflammation, supporting a central role for arginine metabolic control of inflammation.

SUBMITTER: Asosingh K

PROVIDER: S-EPMC7098726 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Arginine metabolic control of airway inflammation.

Asosingh Kewal K Lauruschkat Chris D CD Alemagno Mario M Frimel Matthew M Wanner Nicholas N Weiss Kelly K Kessler Sean S Meyers Deborah A DA Bennett Carole C Xu Weiling W Erzurum Serpil S

JCI insight 20200130 2

Inducible nitric oxide synthase (iNOS) and arginase-2 (ARG2) share a common substrate, arginine. Higher expression of iNOS and exhaled NO are linked to airway inflammation in patients. iNOS deletion in animal models suggests that eosinophilic inflammation is regulated by arginine metabolism. Moreover, ARG2 is a regulator of Th2 response, as shown by the development of severe eosinophilic inflammation in ARG2-/- mice. However, potential synergistic roles of iNOS and ARG2 in asthma have not been e ...[more]

PMID: 31996482

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Project description:BackgroundSystemic immune inflammation is a key mediator in the progression of coronary artery disease (CAD), concerning various metabolic and lipid changes. In this study, the relationship between the inflammatory index and metabolic profile in patients with CAD was investigated to provide deep insights into metabolic disturbances related to inflammation.MethodsWidely targeted plasma metabolomic and lipidomic profiling was performed in 1,234 patients with CAD. Laboratory circulating inflammatory markers were mainly used to define general systemic immune and low-grade inflammatory states. Multivariable-adjusted linear regression was adopted to assess the associations between 860 metabolites and 7 inflammatory markers. Least absolute shrinkage and selection operator (LASSO) logistic-based classifiers and multivariable logistic regression were applied to identify biomarkers of inflammatory states and develop models for discriminating an advanced inflammatory state.ResultsMultiple metabolites and lipid species were linearly associated with the seven inflammatory markers [false discovery rate (FDR) <0.05]. LASSO and multivariable-adjusted logistic regression analysis identified significant associations between 45 metabolites and systemic immune-inflammation index, 46 metabolites and neutrophil-lymphocyte ratio states, 32 metabolites and low-grade inflammation score, and 26 metabolites and high-sensitivity C-reactive protein states (P < 0.05). Glycerophospholipid metabolism and arginine and proline metabolism were determined as key altered metabolic pathways for systemic immune and low-grade inflammatory states. Predictive models based solely on metabolite combinations showed feasibility (area under the curve: 0.81 to 0.88) for discriminating the four parameters that represent inflammatory states and were successfully validated using a validation cohort. The inflammation-associated metabolite, namely, β-pseudouridine, was related to carotid and coronary arteriosclerosis indicators (P < 0.05).ConclusionsThis study provides further information on the relationship between plasma metabolite profiles and inflammatory states represented by various inflammatory markers in CAD. These metabolic markers provide potential insights into pathological changes during CAD progression and may aid in the development of therapeutic targets.

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Arginine metabolic control of airway inflammation.

Publications

Arginine metabolic control of airway inflammation.

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