High D-glucose levels induce ACE2 expression via GLUT1 in human airway epithelial cell line Calu-3

Wakabayashi, Yoshitaka; Nakayama, Shin; Yamamoto, Ai; Kitazawa, Takatoshi

doi:10.1186/s12860-022-00427-4

Cited by 4 publications

(1 citation statement)

References 39 publications

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“…Prolonged inflammatory conditions suppress ACE2 and its product Ang(1-7), which activates MasR and promotes FOXO1 stability and transcriptional activation of antioxidant genes ( 103 ). High glucose levels are associated with increased ACE2 levels in bronchial submucosal cells ( 104 ), and conversely, ACE2 deficiency has been linked to increased glucose utilization ( 104 ). In our model, MHV-1 increased AKT activation, inhibited FOXO1 and ACE2, and promoted GLUT1 production in association with a reduction in blood glucose levels.…”

Section: Discussionmentioning

confidence: 99%

Anti-PD-L1 therapy altered inflammation but not survival in a lethal murine hepatitis virus-1 pneumonia model

Curran,

Cui,

et al. 2024

Front. Immunol.

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IntroductionBecause prior immune checkpoint inhibitor (ICI) therapy in cancer patients presenting with COVID-19 may affect outcomes, we investigated the beta-coronavirus, murine hepatitis virus (MHV)-1, in a lethal pneumonia model in the absence (Study 1) or presence of prior programmed cell death ligand-1 (PD-L1) antibody (PD-L1mAb) treatment (Study 2). MethodsIn Study 1, animals were inoculated intratracheally with MHV-1 or vehicle and evaluated at day 2, 5, and 10 after infection. In Study 2, uninfected or MHV-1-infected animals were pretreated intraperitoneally with control or PD-L1-blocking antibodies (PD-L1mAb) and evaluated at day 2 and 5 after infection. Each study examined survival, physiologic and histologic parameters, viral titers, lung immunophenotypes, and mediator production.ResultsStudy 1 results recapitulated the pathogenesis of COVID-19 and revealed increased cell surface expression of checkpoint molecules (PD-L1, PD-1), higher expression of the immune activation marker angiotensin converting enzyme (ACE), but reduced detection of the MHV-1 receptor CD66a on immune cells in the lung, liver, and spleen. In addition to reduced detection of PD-L1 on all immune cells assayed, PD-L1 blockade was associated with increased cell surface expression of PD-1 and ACE, decreased cell surface detection of CD66a, and improved oxygen saturation despite reduced blood glucose levels and increased signs of tissue hypoxia. In the lung, PD-L1mAb promoted S100A9 but inhibited ACE2 production concomitantly with pAKT activation and reduced FOXO1 levels. PD-L1mAb promoted interferon-γ but inhibited IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production, contributing to reduced bronchoalveolar lavage levels of eosinophils and neutrophils. In the liver, PD-L1mAb increased viral clearance in association with increased macrophage and lymphocyte recruitment and liver injury. PD-L1mAb increased the production of virally induced mediators of injury, angiogenesis, and neuronal activity that may play role in COVID-19 and ICI-related neurotoxicity. PD-L1mAb did not affect survival in this murine model. DiscussionIn Study 1 and Study 2, ACE was upregulated and CD66a and ACE2 were downregulated by either MHV-1 or PD-L1mAb. CD66a is not only the MHV-1 receptor but also an identified immune checkpoint and a negative regulator of ACE. Crosstalk between CD66a and PD-L1 or ACE/ACE2 may provide insight into ICI therapies. These networks may also play role in the increased production of S100A9 and neurological mediators in response to MHV-1 and/or PD-L1mAb, which warrant further study. Overall, these findings support observational data suggesting that prior ICI treatment does not alter survival in patients presenting with COVID-19.

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Section: Discussionmentioning

confidence: 99%

Anti-PD-L1 therapy altered inflammation but not survival in a lethal murine hepatitis virus-1 pneumonia model

Curran,

Cui,

et al. 2024

Front. Immunol.

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Using ex vivo bioengineered lungs to model pathologies and screening therapeutics: A proof‐of‐concept study

Ahmadipour,

Prado,

Hakak‐Zargar

et al. 2024

Biotech & Bioengineering

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Respiratory diseases, claim over eight million lives annually. However, the transition from preclinical to clinical phases in research studies is often hindered, partly due to inadequate representation of preclinical models in clinical trials. To address this, we conducted a proof‐of‐concept study using an ex vivo model to identify lung pathologies and to screen therapeutics in a humanized rodent model. We extracted and decellularized mouse heart‐lung tissues using a detergent‐based technique. The lungs were then seeded and cultured with human cell lines (BEAS‐2B, A549, and Calu3) for 6−10 days, representing healthy lungs, cancerous states, and congenital pathologies, respectively. By manipulating cultural conditions and leveraging the unique characteristics of the cell lines, we successfully modeled various pathologies, including advanced‐stage solid tumors and the primary phase of SARS‐CoV‐2 infection. Validation was conducted through histology, immunofluorescence staining, and pathology analysis. Additionally, our study involved pathological screening of the efficacy and impact of key anti‐neoplastic therapeutics (Cisplatin and Wogonin) in cancer models. The results highlight the versatility and strength of the ex vivo model in representing crucial lung pathologies and screening therapeutics during the preclinical phase. This approach holds promise for bridging the gap between preclinical and clinical research, aiding in the development of effective treatments for respiratory diseases, including lung cancer.

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Getting sweeter: new evidence for glucose transporters in specific cell types of the airway?

Baines

Vasiljevs

Kalsi

2023

American Journal of Physiology-Cell Physiology

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New technologies such as single cell RNA sequencing (scRNAseq) has enabled identification of the mRNA transcripts expressed by individual cells. This review provides insight from recent scRNAseq studies, on the expression of glucose transporters in the epithelial cells of the airway epithelium from trachea to alveolus. The number of studies analysed was limited, not all reported the full range of glucose transporters and there were differences between cells freshly isolated from the airways and those grown in vitro. Furthermore, glucose transporter mRNA transcripts were expressed at lower levels than other epithelial marker genes. Nevertheless, these studies highlighted that there were differences in cellular expression of glucose transporters. GLUT1 was the most abundant of the broadly expressed transporters that included GLUT8, 10 and 13. GLUT9 transcripts were more common in basal cells and GLUT12 in ionocytes/ciliated cells. In addition to alveolar cells, SGLT1 transcripts were present in secretory cells. GLUT3 mRNA transcripts were expressed in a cell cluster that expressed monocarboxylate (MCT2) transporters. Such distributions likely underlie cell specific metabolic requirements to support proliferation, ion transport, mucous secretion, environment sensing and airway glucose homeostasis. These studies have also highlighted the role of glucose transporters in the movement of dehydroascorbic acid/vitamin C/myoinositol/urate which are factors important to the innate immune properties of the airways. Discrepancies remain between detection of mRNAs, protein and function of glucose transporters in the lungs. However, collation of the data from further scRNAseq studies may provide a better consensus and understanding, supported by qPCR, immunohistochemistry and functional experiments.

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High D-glucose levels induce ACE2 expression via GLUT1 in human airway epithelial cell line Calu-3

Cited by 4 publications

References 39 publications

Anti-PD-L1 therapy altered inflammation but not survival in a lethal murine hepatitis virus-1 pneumonia model

Anti-PD-L1 therapy altered inflammation but not survival in a lethal murine hepatitis virus-1 pneumonia model

Using ex vivo bioengineered lungs to model pathologies and screening therapeutics: A proof‐of‐concept study

Getting sweeter: new evidence for glucose transporters in specific cell types of the airway?

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