Organic Cation Transporters in the Lung—Current and Emerging (Patho)Physiological and Pharmacological Concepts

Selo, Mohammed Ali; Sake, Johannes A.; Ehrhardt, Carsten; Salomon, Johanna J.

doi:10.3390/ijms21239168

Cited by 23 publications

(23 citation statements)

References 151 publications

(254 reference statements)

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“…Carnitine is a small water-soluble molecule that possesses important physiological roles including transport of fatty acids into the mitochondrial matrix for -oxidation, while short-chain acylcarnitines (primarily acetylcarnitine) transport organic acids out of the mitochondria and peroxisomes [30,31]. Beyond its role in -oxidation, carnitine also acts as a free radical scavenger [32] and can reduce oxidative stress-induced apoptosis [33]. Carnitine deficiency has been reported to cause pathological symptoms [30].…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…No gender-based differences in OAT3 expression have been reported in humans [ 19 ]. Although much focus has been on the kidney, OATs are localized to almost all epithelial barriers in the body [ 17 , 20 ]. OAT3 is expressed in both human and mouse lung respiratory epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

Probenecid Inhibits Respiratory Syncytial Virus (RSV) Replication

Murray

Bergeron

Jones

et al. 2022

Viruses

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RNA viruses like SARS-CoV-2, influenza virus, and respiratory syncytial virus (RSV) are dependent on host genes for replication. We investigated if probenecid, an FDA-approved and safe urate-lowering drug that inhibits organic anion transporters (OATs) has prophylactic or therapeutic efficacy to inhibit RSV replication in three epithelial cell lines used in RSV studies, i.e., Vero E6 cells, HEp-2 cells, and in primary normal human bronchoepithelial (NHBE) cells, and in BALB/c mice. The studies showed that nanomolar concentrations of all probenecid regimens prevent RSV strain A and B replication in vitro and RSV strain A in vivo, representing a potential prophylactic and chemotherapeutic for RSV.

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“…Although much focus has been on the kidney, OATs are localized to almost all epithelial barriers in the body 19,20 . OAT3 is expressed in both human and mouse lung respiratory epithelial cells.…”

Section: Introductionmentioning

confidence: 99%

Probenecid Inhibits Respiratory Syncytial Virus (RSV) Replication

Murray¹,

Bergeron²,

Jones³

et al. 2022

Preprint

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RNA viruses like SARS-CoV-2, influenza virus, and respiratory syncytial virus (RSV) are dependent on host genes for replication. We investigated if probenecid prophylaxis or treatment inhibited RSV replication in three epithelial cell lines used in RSV studies, i.e., Vero E6 cells, HEp-2 cells, and in primary normal human bronchoepithelial (NHBE) cells, and in BALB/c mice. The studies showed that nanomolar concentrations of all probenecid regimens prevent RSV strain A and RSV B replication in vitro and RSV strain A in vivo, representing a potential prophylactic and chemotherapeutic for RSV.

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Organic Cation Transporters in the Lung—Current and Emerging (Patho)Physiological and Pharmacological Concepts

Cited by 23 publications

References 151 publications

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

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

Probenecid Inhibits Respiratory Syncytial Virus (RSV) Replication

Probenecid Inhibits Respiratory Syncytial Virus (RSV) Replication

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