Targeting the OXE receptor as a potential novel therapy for asthma

Powell, William S.; Rokach, Joshua

doi:10.1016/j.bcp.2020.113930

Cited by 17 publications

(19 citation statements)

References 121 publications

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“…(H) Transcription levels of cholinergic muscarinic M3 receptor (CHRM3) and cholinergic receptor nicotinic alpha 7 (CHRNA7) (n=51) and (I) oxoeicosanoid receptor 1 (OXER1) (n=51). A unique gene expression profile in lung samples from Covid-19 patients who had died was characterized by high levels of pro-inflammatory cholinergic receptors (CHRM3, CHRNA3, and CHRNA5) 9, 110 , low levels of anti-inflammatory cholinergic receptor (CHRNA7) 113 , and high expression of oxoeicosanoid receptor 1 (OXER1) 50 which mediates the pro-inflammatory effects of eicosanoids (Figures S6B, S6C). Other eicosanoid and cholinergic receptors were also differentially expressed in CVL patients compared to the CVH or NCV group (Figures S6A, S6B, S6C).…”

Section: Resultsmentioning

confidence: 99%

“…The involvement of AA was confirmed by bioinformatic analyses that identified the expression or upregulation of genes related to AA metabolism and eicosanoid receptors in some lung biopsies. These included the OXER1 gene, which encodes a receptor for AA and 5-HETE 48 which mediates neutrophil activation/recruitment 49, 50 . Our metabolomic analysis also showed an increase in the plasma AA and linoleic acid levels, similar to a plasma lipidome performed by Schwarz et al, suggesting a strong correlation between lipid mediators and Covid-19 severity 51 .…”

Section: Discussionmentioning

confidence: 99%

“…Abbreviations: CVL, Covid-19 low viral load; CVH, Covid-19 high viral load; NCV, non-Covid-19 viral load 9, 50, 110, 113 .…”

Section: Supplementary Figuresmentioning

confidence: 99%

“…CVL patients displayed increased pulmonary levels of expression of genes associated with the ACh and AA pathways, encoding for cholinergic receptors, the ACh release cycle, AA metabolism, and eicosanoid receptors, compared to CVH or NCV patients. The expression profile of some genes may favour inflammatory events, such as upregulated cholinergic and eicosanoid receptors (CHRM3, CHRNA3, CHRNA5, and OXER1) and low levels of the anti-inflammatory cholinergic receptor (CHRNA7) 9, 50, 110, 113…”

Section: Supplementary Figuresmentioning

confidence: 99%

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Cholinergic and lipid mediators crosstalk in Covid-19 and the impact of glucocorticoid therapy

Pérez

Pimentel

Fuzo

et al. 2021

Preprint

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Cytokine storms and hyperinflammation, potentially controlled by glucocorticoids, occur in COVID-19; the roles of lipid mediators and acetylcholine (ACh) and how glucocorticoid therapy affects their release in Covid-19 remain unclear. Blood and bronchoalveolar lavage (BAL) samples from SARS-CoV-2- and non-SARS-CoV-2-infected subjects were collected for metabolomic/lipidomic, cytokines, soluble CD14 (sCD14), and ACh, and CD14 and CD36-expressing monocyte/macrophage subpopulation analyses. Transcriptome reanalysis of pulmonary biopsies was performed by assessing coexpression, differential expression, and biological networks. Correlations of lipid mediators, sCD14, and ACh with glucocorticoid treatment were evaluated. This study enrolled 190 participants with Covid-19 at different disease stages, 13 hospitalized non-Covid-19 patients, and 39 healthy-participants. SARS-CoV-2 infection increased blood levels of arachidonic acid (AA), 5-HETE, 11-HETE, sCD14, and ACh but decreased monocyte CD14 and CD36 expression. 5-HETE, 11-HETE, cytokines, ACh, and neutrophils were higher in BAL than in circulation (fold-change for 5-HETE 389.0; 11-HETE 13.6; ACh 18.7, neutrophil 177.5, respectively). Only AA was higher in circulation than in BAL samples (fold-change 7.7). Results were considered significant at P<0.05, 95%CI. Transcriptome data revealed a unique gene expression profile associated with AA, 5-HETE, 11-HETE, ACh, and their receptors in Covid-19. Glucocorticoid treatment in severe/critical cases lowered ACh without impacting disease outcome. We first report that pulmonary inflammation and the worst outcomes in Covid-19 are associated with high levels of ACh and lipid mediators. Glucocorticoid therapy only reduced ACh, and we suggest that treatment may be started early, in combination with AA metabolism inhibitors, to better benefit severe/critical patients.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Abbreviations: CVL, Covid-19 low viral load; CVH, Covid-19 high viral load; NCV, non-Covid-19 viral load 9, 50, 110, 113 .…”

Section: Supplementary Figuresmentioning

confidence: 99%

Section: Supplementary Figuresmentioning

confidence: 99%

See 2 more Smart Citations

Cholinergic and lipid mediators crosstalk in Covid-19 and the impact of glucocorticoid therapy

Pérez

Pimentel

Fuzo

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…Of those, S-Y048, which is highly potent and orally bioavailable, demonstrated a significant inhibition of eosinophil infiltration into the skin in response to intradermally administered 5-oxo-ETE and house dust mite in cynomolgus monkeys [ 80 ]. Thus, targeting of 5-oxo-ETE shows potential as a novel therapy for asthma and eosinophil-associated diseases [ 241 ].…”

Section: Eicosanoids and Eosinophilsmentioning

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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A review of non-prostanoid, eicosanoid receptors: expression, characterization, regulation, and mechanism of action

Biringer

2021

J. Cell Commun. Signal.

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Eicosanoid signaling controls a wide range of biological processes from blood pressure homeostasis to inflammation and resolution thereof to the perception of pain and to cell survival itself. Disruption of normal eicosanoid signaling is implicated in numerous disease states. Eicosanoid signaling is facilitated by G-protein-coupled, eicosanoid-specific receptors and the array of associated G-proteins. This review focuses on the expression, characterization, regulation, and mechanism of action of non-prostanoid, eicosanoid receptors.

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Targeting the OXE receptor as a potential novel therapy for asthma

Cited by 17 publications

References 121 publications

Cholinergic and lipid mediators crosstalk in Covid-19 and the impact of glucocorticoid therapy

Cholinergic and lipid mediators crosstalk in Covid-19 and the impact of glucocorticoid therapy

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

A review of non-prostanoid, eicosanoid receptors: expression, characterization, regulation, and mechanism of action

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