Increased mitochondrial arginine metabolism supports bioenergetics in asthma

Xu, Weiling; Ghosh, Sudakshina; Comhair, Suzy; Asosingh, Kewal; Janocha, Allison J.; Mavrakis, Deloris A.; Bennett, Carole; Gruca, Lourdes L.; Graham, Brian B.; Queisser, Kimberly; Kao, Christina C.; Wedes, Samuel H.; Petrich, John M.; Tuder, Rubin M.; Kalhan, Satish C.; Erzurum, Serpil C.

doi:10.1172/jci82925

Cited by 104 publications

(127 citation statements)

References 65 publications

(111 reference statements)

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“…We found that arginine, ornithine, citrulline, creatine, creatinine, hydroxyproline and sarcosine were also affected. This finding was consistent with previous studies that showed that cortisol regulates arginine and glutamine metabolism through a glucocorticoid receptor-mediated mechanism [27,28]. Arginase was of particular importance for competing with nitric oxide synthesis.…”

Section: Discussionsupporting

confidence: 93%

Distinct Metabolic Profile of Inhaled Budesonide and Salbutamol in Asthmatic Children during Acute Exacerbation

Yang

Zhang

et al. 2017

Basic Clin Pharma Tox

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Inhaled budesonide and salbutamol represent the most important and frequently used drugs in asthmatic children during acute exacerbation. However, there is still no consensus about their resulting metabolic derangements; thus, this study was conducted to determine the distinct metabolic profiles of these two drugs. A total of 69 children with asthma during acute exacerbation were included, and their serum and urine were investigated using high-resolution nuclear magnetic resonance (NMR). A metabolomics analysis was performed using a principal component analysis and orthogonal signal correction-partial least squares using SIMCA-P. The different metabolites were identified, and the distinct metabolic profiles were analysed using MetPA. A high-resolution NMR-based serum and urine metabolomics approach was established to study the overall metabolic changes after inhaled budesonide and salbutamol in asthmatic children during acute exacerbation. The perturbed metabolites included 22 different metabolites in the serum and 21 metabolites in the urine. Based on an integrated analysis, the changed metabolites included the following: increased 4-hydroxybutyrate, lactate, cis-aconitate, 5-hydroxyindoleacetate, taurine, trans-4-hydroxy-l-proline, tiglylglycine, 3-hydroxybutyrate, 3-methylhistidine, glucose, cis-aconitate, 2-deoxyinosine and 2-aminoadipate; and decreased alanine, glycerol, arginine, glycylproline, 2-hydroxy-3-methylvalerate, creatine, citrulline, glutamate, asparagine, 2-hydroxyvalerate, citrate, homoserine, histamine, sn-glycero-3-phosphocholine, sarcosine, ornithine, creatinine, glycine, isoleucine and trimethylamine N-oxide. The MetPA analysis revealed seven involved metabolic pathways: arginine and proline metabolism; taurine and hypotaurine metabolism; glycine, serine and threonine metabolism; glyoxylate and dicarboxylate metabolism; methane metabolism; citrate cycle; and pyruvate metabolism. The perturbed metabolic profiles suggest potential metabolic reprogramming associated with a combination treatment of inhaled budesonide and salbutamol in asthmatic children.Glucocorticoids and beta2 agonists represent the most important and frequently used drugs for symptom control in asthmatic children during acute exacerbation [1,2]. Current guidelines recommend the combined use of glucocorticoids and beta2 agonists as the preferred therapy for asthmatic children during acute exacerbation [3,4]. The glucocorticoid and beta2 agonist therapies are effective at controlling airway inflammation, reducing asthma symptoms, decreasing airway hyper-responsiveness and reducing the frequency and severity of exacerbations as well as asthma mortality. Despite their undoubted effectiveness and safety, there is still no consensus about the resulting metabolic derangements, including the development of dyslipidaemia, insulin resistance, glucose intolerance, diabetes, central adiposity and skeletal muscle wasting [5][6][7].Both glucocorticoids and beta2 agonists have the potential to influence glucose, lipid and protein...

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Section: Discussionsupporting

confidence: 93%

Distinct Metabolic Profile of Inhaled Budesonide and Salbutamol in Asthmatic Children during Acute Exacerbation

Yang

Zhang

et al. 2017

Basic Clin Pharma Tox

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“…Over the past few years, accumulating evidence suggests that changes in metabolism regulates inflammation and T cell function (2). Current concepts suggest that arginine metabolism affects immune cell function via both mitochondrial and nonmitochondrial mechanisms of action (3,4). Recently, our group identified that arginine metabolism is a key driver of Th2 airway inflammation (4).…”

Section: Introductionmentioning

confidence: 99%

Arginine metabolic control of airway inflammation

Asosingh¹,

Lauruschkat²,

Alemagno³

et al. 2020

JCI Insight

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“…Module D2 inversely correlated with current asthma status (Figures 3C and 3G). GO BP analysis of genes in this module revealed mainly RNA processing and metabolic pathways (Figure 3C), perhaps reflecting an imprint of systemic metabolic changes linked to asthma status (Adamko et al, 2016; Xu et al, 2016). Module E2 was positively correlated with age and weight (not BMI) at the time of the ARTI and study visit (Figures 3D and 3I).…”

Section: Resultsmentioning

confidence: 99%

Genomic Circuitry Underlying Immunological Response to Pediatric Acute Respiratory Infection

et al. 2018

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SUMMARY Acute respiratory tract viral infections (ARTIs) cause significant morbidity and mortality. CD8 T cells are fundamental to host responses, but transcriptional alterations underlying anti-viral mechanisms and links to clinical characteristics remain unclear. CD8 T cell transcriptional circuitry in acutely ill pediatric patients with influenza-like illness was distinct for different viral pathogens. Although changes included expected upregulation of interferon-stimulated genes (ISGs), transcriptional downregulation was prominent upon exposure to innate immune signals in early IFV infection. Network analysis linked changes to severity of infection, asthma, sex, and age. An influenza pediatric signature (IPS) distinguished acute influenza from other ARTIs and outperformed other influenza prediction gene lists. The IPS allowed a deeper investigation of the connection between transcriptional alterations and clinical characteristics of acute illness, including age-based differences in circuits connecting the STAT1/2 pathway to ISGs. A CD8 T cell-focused systems immunology approach in pediatrics identified age-based alterations in ARTI host response pathways.

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Increased mitochondrial arginine metabolism supports bioenergetics in asthma

Cited by 104 publications

References 65 publications

Distinct Metabolic Profile of Inhaled Budesonide and Salbutamol in Asthmatic Children during Acute Exacerbation

Distinct Metabolic Profile of Inhaled Budesonide and Salbutamol in Asthmatic Children during Acute Exacerbation

Arginine metabolic control of airway inflammation

Genomic Circuitry Underlying Immunological Response to Pediatric Acute Respiratory Infection

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