prostaglandin-d2 and Rhinitis--Allergic

Prostaglandin D. The role of DP. Head-to-head studies that compare DP

Topics: Adult; Animals; Anti-Allergic Agents; Asthma; Child; Drug Design; Humans; Mast Cells; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Rhinitis, Allergic

By activating DP1 and DP2 receptors on immune and non-immune cells, prostaglandin D2 (PGD2), a major metabolic product of cyclo-oxygenase pathway released after IgE-mediated mast cell activation, has pro-inflammatory effects, which are relevant to the pathophysiology of allergic airway disease. At least 15 selective, orally active, DP2 receptor antagonists and one DP1 receptor antagonist (asapiprant) are under development for asthma and/or allergic rhinitis.. In this review, the authors cover the pharmacology of PGD2 and PGD2 receptor antagonists and look at the preclinical, phase I and phase II studies with selective DP1 and DP2 receptor antagonists.. Future research should aim to develop once daily compounds and increase the drug clinical potency which, apart from OC000459 and ADC-3680, seems to be relatively low. Further research and development of DP2 receptor antagonists is warranted, particularly in patients with severe uncontrolled asthma, whose management is a top priority. Pediatric studies, which are not available, are required for assessing the efficacy and safety of this novel drug class in children with asthma and allergic rhinitis. Studies on the efficacy of DP2 receptor antagonists in various asthma phenotypes including: smokers, obese subjects, early vs late asthma onset, fixed vs reversible airflow limitation, are required for establishing their pharmacotherapeutic role.

Topics: Animals; Asthma; Child; Drug Design; Drugs, Investigational; Humans; Inflammation; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Rhinitis, Allergic

Allergic rhinitis (AR) is a common type of inflammatory disease with symptoms including rhinorrhea, fatigue, sneezing, and disturbed sleep. AR affects nearly 40% of peoples worldwide with the increased numbers of new cases. In this work, the study was conducted to disclose the anti-inflammatory and antiallergic properties of cirsilineol against the ovalbumin (OVA)-sensitized AR in mice. AR was provoked in BALB/c mice through the OVA challenge 30 days along with 10 and 20 mg/kg of cirsilineol treatment. The nasal symptoms, i.e., rubbing and sneezing was monitored after the final OVA challenge. The status of OVA-specific IgE, PGD2, and LTC4 was investigated using assay kits. The status of pro-inflammatory markers also examined using assay kits. The levels of oxidative markers, SOD activity, and pro-inflammatory markers in the spleen mononuclear cells (SMEs) were studied by using respective assay kits. The mRNA expression of TXNIP was assessed using RT-PCR study. The 10 and 20 mg/kg of cirsilineol treatment effectively decreased the sneezing and nasal rubbings in OVA-provoked mice. Cirsilineol also decreased the IgE, PGD2, and LTC4 status in the AR animals. The status of pro-inflammatory markers, i.e., IL-4, IL-5, IL-6, IL-33 and TNF-α was found to be decreased in the cirsilineol administered AR mice. Cirsilineol effectively reduced the ROS and MDA and improved SOD in the OVA-challenged SMCs. The mRNA expression of TXNIP was appreciably suppressed by the cirsilineol treatment. Altogether, these findings proved the beneficial actions of cirsilineol against the OVA-triggered AR in mice. The additional studies on the cirsilineol could lead to the development of new drug for AR management.

Topics: Animals; Anti-Allergic Agents; Biomarkers; Carrier Proteins; Cells, Cultured; Disease Models, Animal; Eosinophils; Flavones; Histamine; Immunoglobulin E; Leukotriene C4; Mice, Inbred BALB C; Nasal Lavage Fluid; Ovalbumin; Oxidative Stress; Prostaglandin D2; Rhinitis, Allergic; Spleen; Thioredoxins

Nasal obstruction is one of the most bothersome symptoms of allergic rhinitis (AR) affecting sleep-related quality of life in AR patients. Although several treatments were tested to control nasal obstruction, some patients with moderate to severe AR do not respond to current treatments, including the combined administration of different types of anti-allergic medicine. Thus, new options for AR treatment are needed. This study aimed to evaluate the effects of combined treatment with a novel inhibitor of hematopoietic prostaglandin D synthase (HPGDS), TAS-205, and different types of anti-allergic medicine on nasal obstruction in AR. Firstly, we demonstrated that TAS-205 selectively inhibited prostaglandin D

Topics: Acetates; Animals; Anti-Allergic Agents; Cell Line; Cyclopropanes; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Guinea Pigs; Humans; Intramolecular Oxidoreductases; Lipocalins; Male; Morpholines; Nasal Mucosa; Nasal Obstruction; Ovalbumin; Piperidines; Prostaglandin D2; Pyrroles; Quality of Life; Quinolines; Rats; Rhinitis, Allergic; Sulfides; Terfenadine

Group 2 innate lymphoid cells (ILC2s) play important roles in allergic inflammation. However, their roles in the pathophysiology of allergic rhinitis (AR) are poorly understood.. Prevalence of ILC2s in the inferior nasal turbinate (INT) tissues and the activating mechanisms of ILC2s were examined in patients with house dust mite (HDM)-induced AR.. Eighteen patients with HDM-induced AR and 13 control subjects were recruited. Fresh INT tissues and peripheral blood mononuclear cells (PBMCs) were analysed using flow cytometry. Nasal lavage fluids (NLF) were collected at 10 minutes after the nasal provocation test (NPT) with HDM disc, and released mediators were measured by ELISA. Sorted ILC2s were cultured and stimulated with mediators associated with AR.. The prevalence of ILC2s was significantly increased in nasal mucosa of patients with HDM-induced AR, and it was positively correlated with the number of infiltrating eosinophils. ILC2s in the INT tissues expressed a prostaglandin D. PGD

Topics: Allergens; Animals; Biomarkers; Case-Control Studies; Cysteine; Cytokines; Disease Susceptibility; Female; Humans; Immunity, Innate; Immunophenotyping; Leukotrienes; Lymphocyte Count; Male; Mucous Membrane; Nasal Lavage Fluid; Prostaglandin D2; Pyroglyphidae; Rhinitis, Allergic; Th2 Cells

Conventional allergic rhinitis (AR) treatments have limitations due to the lack of safety and complete cure strategy. We evaluated the effects of silent information regulator 1 (SIRT1), a multifunctional molecule involved in a variety of inflammatory pathways, on murine AR model. Ovalbumin (OVA)-induced murine model was constructed, and recombinant SIRT1 was administered into the nostril continuously. The expression of SIRT1 was measured at mRNA and protein levels, and the allergic symptoms were evaluated. Protein levels of OVA-specific IgE, leukotriene C4 (LTC4), eosinophil cation protein (ECP), prostaglandin D2 (PGD2), as well as different inflammatory cytokine mediators in the serum and nasal lavage fluid (NLF), were assessed by ELISA. The effects of SIRT1 on human primary nasal epithelial cells challenged with tumour necrosis factor (TNF)-α were also evaluated by investigating the HMGB1/TLR4 signalling pathway. Administration of SIRT1 significantly alleviated OVA-induced AR symptoms with lower numbers of sneezing and nasal rubbing events, decreased levels of OVA-specific IgE, LTC4, ECP, PGD2, less inflammatory cells and downregulated levels of Th2 type cytokines. SIRT1 also reduced the genes of HMGB1/TLR4 signalling pathway in the murine model and cultured human nasal epithelial cells. Expression of SIRT1 is impaired in OVA-induced AR model. The administration of SIRT1 alleviates the allergic symptoms of mice, regulates the production of pro-inflammatory mediators predominantly produced by Th2 cells in AR and attenuates expressions of proteins relevant to HMGB1/TLR4 signalling pathway. All the results showed that SIRT1 is promising as a therapeutic agent of AR.

Topics: Animals; Cells, Cultured; Disease Models, Animal; Down-Regulation; Eosinophil Cationic Protein; Female; HMGB1 Protein; Humans; Immunoglobulin E; Leukotriene C4; Mice; Mice, Inbred BALB C; Nasal Lavage Fluid; Nasal Mucosa; Ovalbumin; Prostaglandin D2; Recombinant Proteins; Rhinitis, Allergic; Signal Transduction; Sirtuin 1; Th2 Cells; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

Food allergy is immediate hypersensitive reactions to ingested foods. Since early diagnosis is effective for disease control, development of an objective diagnostic index is required. Using mediator-lipidomics, we found that levels of the urinary prostaglandin D

Topics: Animals; Asthma; Dermatitis, Atopic; Food Hypersensitivity; Humans; Hyperplasia; Intestines; Intramolecular Oxidoreductases; Lipocalins; Mast Cells; Mice; Mice, Inbred BALB C; Ovalbumin; Prostaglandin D2; Rhinitis, Allergic

We recently shown a novel neuro-immune competition between vasoactive intestinal peptide (VIP) and PGD2 for CRTH2 receptor, and that genistein augmented VIP and PGD2-induced eosinophil chemotaxis. However, there are neither studies on the CRTH2 gene expression in allergic rhinitis (AR) nor in the effect of tyrosine kinase inhibitors in CRTH2 gene regulation. Our Objectives were to study the gene expression modulation of CRTH2 receptor in AR patients and the effect of tyrosine kinase inhibitors (TKIs) on CRTH2 gene modulation. Nasal provocation tests, ELISA, qRT-PCR, western blot, flow cytometry and chemotaxis assays in modified micro-Boyden chambers, were all used, to achieve our objectives. Herein we show that AR patients increased the amounts of VIP and PGD2 in their nasal secretions in the early phase reaction, however CRTH2 gene expression from leukocytes recovered in their nasal secretions was upregulated only during the late phase reaction. The TKIs; Genistein, Erbstatin and Herbimycin A, induced the gene expression of CRTH2 and increased the protein content of CRTH2 in both human lymphocytes and eosinophils. This was functional as PGD2/VIP-induced eosinophil chemotaxis was augmented by the TKIs and inhibited by pervanadate, the tyrosine phosphatase inhibitor. These results open channels for therapeutic modalities targeting CRTH2 molecules in AR.

Topics: Adult; Antigens, Dermatophagoides; Cell Movement; Cells, Cultured; Eosinophils; Female; Gene Expression Regulation; Genistein; Humans; Hydroquinones; Lymphocytes; Male; Nasal Mucosa; Neuroimmunomodulation; Prostaglandin D2; Protein Kinase Inhibitors; Receptors, Immunologic; Receptors, Prostaglandin; Rhinitis, Allergic; Rifabutin; Vasoactive Intestinal Peptide

Prostaglandin D2(PGD2) is involved in the pathogenesis of allergic rhinitis. However, the sensory nervous system-mediated contributions of PGD2to the symptoms of allergic rhinitis remain unclear. We investigated the involvement of PGD2in these symptoms and in neuronal excitation by in vivo and ex vivo experiments. In an ovalbumin-induced model of allergic rhinitis in guinea pigs, the number of sneezing, nasal rubbing, and nasal secretion events were assessed after the nasal cavity instillation of PGD2, histamine, or a combination of PGD2and histamine. In situ hybridization for PGD2receptor 1 (DP1) mRNA transcripts and immunohistochemical analysis of histamine H1receptor protein expression in guinea pig trigeminal ganglion (TRG) were performed. The effects of DP1receptor activation on the excitability of TRG neurons to electrical and histamine stimuli were assessed using whole-cell patch-clamp recordings. Histamine induced more sneezing, nasal rubbing, and nasal secretion events than PGD2 PGD2augmented histamine-induced responses, whereas pretreatment with a DP1receptor-selective antagonist completely suppressed PGD2-induced augmentation. DP1receptor mRNA transcripts and H1receptor protein expression could be detected in TRG neurons. Moreover, a DP1receptor agonist caused significant increases in the number of histamine-induced action potentials and depolarization, and reduced the current threshold in small-diameter neurons. Our findings show that PGD2-DP1receptor signaling augments the symptoms of allergic rhinitis via the sensory nervous system by modulating nasal neuronal activation to various stimuli, such as histamine. These findings suggest that DP1receptor antagonist has therapeutic potential for the treatment of allergic rhinitis.

Topics: Action Potentials; Animals; Behavior, Animal; Electric Stimulation; Guinea Pigs; Histamine; Male; Neurons; Ovalbumin; Patch-Clamp Techniques; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Rhinitis, Allergic; Sneezing; Trigeminal Ganglion

Prostaglandin D2 (PGD2 ) plays an important role in allergic inflammation. The PGD2 receptor, CRTH2, is expressed on basophils, eosinophils, and Th2 lymphocytes and mediates chemotactic activity.. To define the role of CRTH2 in allergen-induced nasal responses in a mouse model of allergic rhinitis (AR), a potent, selective CRTH2 receptor antagonist, ARRY-063 was administered in a model of allergic rhinitis in mice.. ARRY-063 was administered orally to ovalbumin (OVA) sensitized and challenged mice. To assess nasal obstruction, respiratory frequency (RF) was monitored by whole-body plethysmography immediately after the 4th challenge (early-phase response, EPR) and 24 h after the 6th challenge (late-phase response, LPR). Nasal resistance (RNA ) was also measured in the LPR. PGD2 was administered with or without OVA to determine the effect of PGD2 on nasal responsiveness. Cytokine levels and histopathological changes in nasal tissue were analysed.. Instillation of PGD2 in the nose of sensitized mice together with a low concentration of OVA induced both an EPR and LPR. Treatment with the CRTH2 receptor antagonist prevented the decreases in RF seen immediately following the 4th challenge of sensitized mice (EPR). In the LPR, decreases in RF and increases in RNA were also prevented by antagonist treatment associated with reduced cytokine levels and inflammation in nasal tissues.. These data identify PGD2 as a mediator of both the EPR and LPR in this model of AR and suggest that antagonism of CRTH2 prevents the development of both the EPR and LPR as well as nasal inflammation.

Topics: Allergens; Animals; Disease Models, Animal; Eosinophils; Female; Mice; Nasal Mucosa; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Rhinitis, Allergic

Biyeom-Tang, a medicine prescribed by oriental clinics, has been used for the treatment of the allergic rhinitis (AR). In the present study, an ethanol extract of Biyeom-Tang (EBT) was investigated for anti-allergic properties on bone-marrow derived mast cells (BMMC) and in vivo models.. The anti-allergic properties of EBT were evaluated by measuring β-Hex release and the production of prostaglandin D2 (PGD2) and leukotriene C4 (LTC4) on BMMC in vitro and PCA and OVA-induced AR models in vivo.. EBT strongly inhibited a degranulation reaction in a dose dependent manner with an IC50 value of 35.6 μg/ml. In addition, the generation of PGD2 and LTC4 was inhibited in BMMC in a concentration-dependent manner with IC50 values of 7.0 μg/ml and 10.9 μg/ml, respectively. When administrated orally, EBT ameliorated the mast cell-mediated PCA reaction. In the OVA-induced AR model, the increased levels of IgE were reduced by EBT. The levels of cytokines, such as IL-4, IL-5, IL-10, and IL-13 decreased in the splenocytes of EBT-treated mice. The histological analysis shows that the infiltration of inflammatory cells increased by OVA-sensitization was also reduced.. Taken together, these results suggested that EBT has anti-allergic and anti-inflammatory effects in vitro and in vivo models.

Topics: Angelica; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Bone Marrow Cells; Disease Models, Animal; Female; Immunoglobulin E; Interleukins; Male; Mast Cells; Medicine, Korean Traditional; Mentha; Mice, Inbred BALB C; Mice, Inbred ICR; Phytotherapy; Plant Extracts; Prostaglandin D2; Rhinitis, Allergic; Trichosanthes; Xanthium