Autocrine activity of cysteinyl leukotrienes in human vascular endothelial cells: Signaling through the CysLT2 receptor

Capra, Valérie; Carnini, Chiara; Accomazzo, Maria Rosa; Gennaro, Antonio Di; Fiumicelli, Marco; Borroni, Emanuele; Brivio, I.; Buccellati, Carola; Mangano, Paolo; Carnevali, Silvia; Rovati, G. Enrico; Sala, Angelo

doi:10.1016/j.prostaglandins.2015.03.007

Cited by 18 publications

(11 citation statements)

References 62 publications

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“…In this model, CysLT 2 mediated inflammatory reactions in a vascular bed-specific manner by altering transendothelial vesicle transport-based vascular permeability. Further reports corroborate CysLT/CysLT 2 -induced permeability of human vascular endothelial cells (164).…”

Section: Cyslts and Cognate Receptors In Health And Diseasessupporting

confidence: 72%

Leukotriene receptors as potential therapeutic targets

Yokomizo

Nakamura

Shimizu

2018

Journal of Clinical Investigation

146

122

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Leukotrienes, a class of arachidonic acid-derived bioactive molecules, are known as mediators of allergic and inflammatory reactions and considered to be important drug targets. Although an inhibitor of leukotriene biosynthesis and antagonists of the cysteinyl leukotriene receptor are clinically used for bronchial asthma and allergic rhinitis, these medications were developed before the molecular identification of leukotriene receptors. Numerous studies using cloned leukotriene receptors and genetically engineered mice have unveiled new pathophysiological roles for leukotrienes. This Review covers the recent findings on leukotriene receptors to revisit them as new drug targets.

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Section: Cyslts and Cognate Receptors In Health And Diseasessupporting

confidence: 72%

Leukotriene receptors as potential therapeutic targets

Yokomizo

Nakamura

Shimizu

2018

Journal of Clinical Investigation

146

122

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“…Of note, the protective effect induced by CysLT 2 receptor antagonism was similar to that of pranlukast. In the latter context, it should be considered that pranlukast, zafirlukast and pobilukast have been found to be partially active also at the CysLT 2 receptor (Heise et al ., ; Wunder et al ., ; Capra et al ., ).…”

Section: Cyslt Receptorsmentioning

confidence: 97%

Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7

Bäck

Powell

Dahlén

et al. 2014

British J Pharmacology

182

146

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The endogenous ligands for the LT, lipoxin (LX) and oxoeicosanoid receptors are bioactive products produced by the action of the lipoxygenase family of enzymes. The LT receptors BLT1 and BLT2, are activated by LTB4 and the CysLT1 and CysLT2 receptors are activated by the cysteinyl‐LTs, whereas oxoeicosanoids exert their action through the OXE receptor. In contrast to these pro‐inflammatory mediators, LXA4 transduces responses associated with the resolution of inflammation through the receptor FPR2/ALX (ALX/FPR2). The aim of the present review is to give a state of the field on these receptors, with focus on recent important findings. For example, BLT1 receptor signalling in cancer and the dual role of the BLT2 receptor in pro‐ and anti‐inflammatory actions have added more complexity to lipid mediator signalling. Furthermore, a cross‐talk between the CysLT and P2Y receptor systems has been described, and also the presence of novel receptors for cysteinyl‐LTs, such as GPR17 and GPR99. Finally, lipoxygenase metabolites derived from ω‐3 essential polyunsaturated acids, the resolvins, activate the receptors GPR32 and ChemR23. In conclusion, the receptors for the lipoxygenase products make up a sophisticated and tightly controlled system of endogenous pro‐ and anti‐inflammatory signalling in physiology and pathology.

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“…LTB 4 is likely one of the key mediators carrying out the huge influx of these cells to airways, which leads to the profound blood lymphocytopenia observed in severe COVID-19 and neutrophilia in airways ( Zhang et al, 2020 ; Li et al, 2020 ). Moreover, the cysteinyl leukotrienes (cysLTs) LTC 4 and LTD 4 are among the most profound vascular leakage promoting agents in man and animal models, signaling via two GPCR subtypes CysLT 1 and CysLT 2 ( Samuelsson et al, 1987 ; Funk, 2001 ; Maekawa et al, 2002 ; Lee et al, 2004 ; Moos et al, 2008 ; Capra et al, 2015 ). CysLTs also provoke a number of immune cell actions e.g., macrophage activation, inflammatory cell cytokine secretion and activation of the transcription factor NF-κB, which controls numerous genes involved in inflammation, all of which would heighten the hyperimmune/inflammatory response ( Kanaoka and Boyce, 2004 ; Maeba et al, 2005 ; Tahan et al, 2008 ) in COVID-19.…”

Section: Mechanistic Pathways Explaining Covid-19 Progression That Inmentioning

confidence: 99%

A Novel Strategy to Mitigate the Hyperinflammatory Response to COVID-19 by Targeting Leukotrienes

Funk

Ardakani²

2020

Front. Pharmacol.

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SARS-CoV-2 causing coronavirus disease 2019 (COVID-19) has wreaked havoc during the global pandemic of 2020 infecting millions and leaving over a half million dead. As a new virus, not previously in the human population, but with similarities to other coronaviruses causing severe acute respiratory distress syndrome (SARS/ARDS), and no known treatments, the race to re-purpose existing drugs and to enlist novel therapeutics is underway. In the half-year since the first cases, we have acquired substantial knowledge of this virus and the clinical course of COVID-19 progression. Results from early clinical trials have revealed two treatments (remdesivir, dexamethasone) that mitigate disease progression but clearly, there is much room for improvement. Initial case reports indicated many succumb to COVID-19 of hypoxic respiratory failure due to ARDS. However, ensuing studies revealed an atypical, immune cell-sequestered, vasculature-inflamed state leading to multiorgan thrombotic complications and end organ failure likely due to hyperinflammatory host responses. This Perspective focuses on a potential mechanism for a key COVID-19 disease progression turning point related to vascular and airway inflammation. The leukotriene lipid mediators have been overlooked with discussion centering on cytokine storms unleashing the deadly form of COVID-19. Leukotrienes possess some of the most potent known activities on immune cell trafficking and vascular leakage. We offer a simple treatment paradigm using two generic drugs targeting the hyperinflammatory response that characterizes the turning point from mild to severe/critical COVID-19 by targeting leukotriene biosynthesis with zileuton (Zyflo ® controlled release formulation) and antagonism of the cysteinyl leukotriene 1 receptor with montelukast (Singulair ®).

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Autocrine activity of cysteinyl leukotrienes in human vascular endothelial cells: Signaling through the CysLT2 receptor

Cited by 18 publications

References 62 publications

Leukotriene receptors as potential therapeutic targets

Leukotriene receptors as potential therapeutic targets

Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7

A Novel Strategy to Mitigate the Hyperinflammatory Response to COVID-19 by Targeting Leukotrienes

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