The pharmacology of the prostaglandin D2 receptor 2 (DP2) receptor antagonist, fevipiprant

Brightling, Christopher E.; Kulkarni, Swarupa G.; Lambrecht, Bart; Sandham, David A.; Weiss, Michel; Altman, Pablo

doi:10.1016/j.pupt.2021.102030

Cited by 6 publications

(7 citation statements)

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“…In addition, the activity of mediators released by mast cells can also be blocked by receptor antagonists such as fevipiprant, the PGD2 receptor antagonist. Because PGD2 receptors are expressed on airway epithelium, smooth muscle, and various immune cells, blocking these receptors has produced favorable results in clinical trials by reducing asthma complications such as eosinophil infiltration and airway remodeling [ 123 ]. Another approach to combat mast cell-related disease is to target mast cell activation altogether.…”

Section: Mast Cell Mediators As Therapeutic Targetsmentioning

confidence: 99%

The role of human mast cells in allergy and asthma

et al. 2022

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Mast cells are tissue-inhabiting cells that play an important role in inflammatory diseases of the airway tract. Mast cells arise in the bone marrow as progenitor cells and complete their differentiation in tissues exposed to the external environment, such as the skin and respiratory tract, and are among the first to respond to bacterial and parasitic infections. Mast cells express a variety of receptors that enable them to respond to a wide range of stimulants, including the high-affinity FcεRI receptor. Upon initial contact with an antigen, mast cells are sensitized with IgE to recognize the allergen upon further contact. FcεRI-activated mast cells are known to release histamine and proteases that contribute to asthma symptoms. They release a variety of cytokines and lipid mediators that contribute to immune cell accumulation and tissue remodeling in asthma. Mast cell mediators trigger inflammation and also have a protective effect. This review aims to update the existing knowledge on the mediators released by human FcεRI-activated mast cells, and to unravel their pathological and protective roles in asthma and allergy. In addition, we highlight other diseases that arise from mast cell dysfunction, the therapeutic approaches used to address them, and fill the gaps in our current knowledge. Mast cell mediators not only trigger inflammation but may also have a protective effect. Given the differences between human and animal mast cells, this review focuses on the mediators released by human FcεRI-activated mast cells and the role they play in asthma and allergy.

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Section: Mast Cell Mediators As Therapeutic Targetsmentioning

confidence: 99%

The role of human mast cells in allergy and asthma

et al. 2022

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“…To do so we utilized DK-PGD2, which binds selectively to CRTH2 and not DP1 (a closely related prostanoid receptor also capable of binding PGD2). (4) In a microplate-based kinetic fluorescence assay measuring ROS, DK-PGD2 dose-dependently stimulated ROS production in isolated neutrophils. The measured half-maximal effective concentration (EC 50 ) was approximately 40 nM, similar to a previously reported value (54 nM) that was obtained in HEK293 cells expressing human CRTH2.…”

Section: Resultsmentioning

confidence: 99%

“…Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2, also called DP2, CD294, GPR44, and PTGDR2) is a seven-membrane spanning G-protein coupled receptor (GPCR) expressed on type 2 immune cells such as eosinophils, mast cells, Th2 cells, and type 2 innate lymphoid cells (ILC2s). (3)(4)(5) Upon activation with its endogenous ligand, prostaglandin D 2 (PGD 2 ), CRTH2 signals through G i α, leading to increases in cytosolic calcium and reduction in cAMP levels. (4) In eosinophils, CRTH2 agonism promotes inflammatory responses including degranulation and chemotaxis.…”

Section: Introductionmentioning

confidence: 99%

“…(3)(4)(5) Upon activation with its endogenous ligand, prostaglandin D 2 (PGD 2 ), CRTH2 signals through G i α, leading to increases in cytosolic calcium and reduction in cAMP levels. (4) In eosinophils, CRTH2 agonism promotes inflammatory responses including degranulation and chemotaxis. (3) CRTH2 ligation similarly activates ILCs and Th2 cells, leading to chemotaxis, suppression of apoptosis, and synthesis of type 2 cytokines including IL-4, IL-5, IL-9, and IL-13.…”

Section: Introductionmentioning

confidence: 99%

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A dual role for CRTH2 in acute lung injury

Jung

Cohen

Howell

et al. 2022

Preprint

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Acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition defined by rapid onset respiratory failure following acute lung injury (ALI). Its increased incidence due to COVID-19 and high mortality rate (~40%) make the study of ARDS pathogenesis a crucial research priority. CRTH2 is a G protein-coupled receptor with established roles in type 2 immunity and well-characterized inhibitors. Prior studies have shown it also promotes neutrophilic inflammation, indicating that CRTH2 inhibition may be a potential therapeutic strategy for ARDS. To test this hypothesis, we first examined the expression pattern of CRTH2 on murine neutrophils. We found it is expressed on neutrophils, but only after extravasation into the lung. Next, we showed that extravasated lung neutrophils generate inflammatory responses upon stimulation with the CRTH2-specific agonist DK-PGD2, as demonstrated by reactive oxygen species (ROS) production. This response was abrogated in CRTH2 KO neutrophils. Inhibition of CRTH2 with fevipiprant suppressed baseline ROS production, indicating an autocrine PGD2-CRTH2 signaling loop. We then evaluated the role of CRTH2 in vivo using a murine model of LPS-induced ALI. Despite the pro-inflammatory effects of CRTH2 on neutrophils in vitro, we observed exacerbation of lung injury in CRTH2-deficient mice in terms of neutrophilic inflammation, vascular leak, and survival. Bulk RNAseq of lung tissue indicated an impairment in type 2 immune signaling; qPCR and ELISA confirmed downregulation of the key type 2 effector cytokine, IL-4. Thus, CRTH2 appears to play a dual role in ALI, directly promoting neutrophil effector responses, but indirectly suppressing lung injury and neutrophilic inflammation through type 2 immunity. These findings reveal a novel protective function for CRTH2 during lung injury and argue against the use of CRTH2 inhibitors in ARDS.

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“…While Phase II studies in patients with asthma showed fevipiprant reduced sputum eosinophilia, improved lung function, as well as symptoms and quality of life, this efficacy was not replicated in a worldwide Phase 3 clinical trial programme. 283 Nevertheless, there may be patient subgroups that benefit from fevipiprant and future studies are awaited.…”

Section: Current Real-world Understanding Of Biologics In Asthmamentioning

confidence: 99%

Recent Insights into the Management of Inflammation in Asthma

Rupani¹,

Fong²,

Kyyaly³

et al. 2021

JIR

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The present prevailing inflammatory paradigm in asthma is of T2-high inflammation orchestrated by key inflammatory cells like Type 2 helper lymphocytes, innate lymphoid cells group 2 and associated cytokines. Eosinophils are key components of this T2 inflammatory pathway and have become key therapeutic targets. Real-world evidence on the predominant T2-high nature of severe asthma is emerging. Various inflammatory biomarkers have been adopted in clinical practice to aid asthma characterization including airway measures such as bronchoscopic biopsy and lavage, induced sputum analysis, and fractional exhaled nitric oxide. Blood measures like eosinophil counts have also gained widespread usage and multicomponent algorithms combining different parameters are now appearing. There is also growing interest in potential future biomarkers including exhaled volatile organic compounds, micro RNAs and urinary biomarkers. Additionally, there is a growing realisation that asthma is a heterogeneous state with numerous phenotypes and associated treatable traits. These may show particular inflammatory patterns and merit-specific management approaches that could improve asthma patient outcomes. Inhaled corticosteroids (ICS) remain the mainstay of asthma management but their use earlier in the course of disease is being advocated. Recent evidence suggests potential roles for ICS in combination with long-acting beta-agonists (LABA) for as needed use in mild asthma whilst maintenance and reliever therapy regimes have gained widespread acceptance. Other anti-inflammatory strategies including ultra-fine particle ICS, leukotriene receptor antagonists and macrolide antibiotics may show efficacy in particular phenotypes too. Monoclonal antibody biologic therapies have recently entered clinical practice with significant impacts on asthma outcomes. Understanding of the efficacy and use of those agents is becoming clearer with a growing body of real-world evidence as is their potential applicability to other treatable comorbid traits. In conclusion, the evolving understanding of T2 driven inflammation alongside a treatable traits disease model is enhancing therapeutic approaches to address inflammation in asthma.

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The pharmacology of the prostaglandin D2 receptor 2 (DP2) receptor antagonist, fevipiprant

Cited by 6 publications

References 58 publications

The role of human mast cells in allergy and asthma

The role of human mast cells in allergy and asthma

A dual role for CRTH2 in acute lung injury

Recent Insights into the Management of Inflammation in Asthma

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