Dataset Information

Therapeutic Effect of C-C Chemokine Receptor Type 1 (CCR1) Antagonist BX471 on Allergic Rhinitis.

ABSTRACT: Objective and Design:Allergic rhinitis (AR) is an immunoglobulin E (IgE)-mediated inflammatory respiratory hypersensitivity characterized by elevated Th2 cytokines and infiltration of inflammatory cells to nasal tissues. BX471 is a small-molecule C-C chemokine receptor type 1 (CCR1) antagonist involved in suppression of inflammation via blocking of primary ligands. In this study, we examined the anti-inflammatory effect of BX471 on ovalbumin (OVA)-induced AR mice model. Materials and Methods:Levels of OVA-specific IgE and Th1 cytokines were determined by enzyme-linked immunosorbent assay (ELISA). Nasal expression of proinflammatory mediators was assessed by real-time polymerase chain reaction (RT-qPCR). Nasal-cavity sections were stained with hematoxylin and eosin (HE) and periodic acid-Schiff (PAS) to study eosinophil infiltration and goblet cell metaplasia. Relative protein levels of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB), Toll-like Receptor 4 (TLR4) and Toll-like-receptor 2 (TLR2) were assessed by Western Blot. Percentage of CD4+CD25+Foxp3+ T regulatory cells (Treg) was measured by flow cytometry. Results:Mice treated with BX471 showed significantly relieved sneezing and nasal-rubbing behaviors. The expression of nasal proinflammatory factors was significantly downregulated by BX471, and protein levels of tumor necrosis factor alpha (TNF- ?) and NF-kB were suppressed. Blockade of CCR1 ligands inhibited eosinophil recruitment in nasal cavity. In addition, Treg cells population were upregulated in BX471-treated mice. Conclusion:BX471 exerts anti-inflammatory effects in a mouse model of AR by inhibiting CCR1-mediated TNF-? production, which subsequently suppresses NF-kB activation in inflammatory cells, leading to a decrease in Th2 cytokines, IL-1?, VCAM-1, GM-CSF, RANTES, and MIP-1? expression levels, thus inhibiting eosinophil recruitment to nasal mucosa. In addition, BX-471 exhibits anti-allergic effect by increasing Treg cell population. Overall, BX471 represents a promising therapeutic strategy against AR.

SUBMITTER: Feng S

PROVIDER: S-EPMC7398876 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Therapeutic Effect of C-C Chemokine Receptor Type 1 (CCR1) Antagonist BX471 on Allergic Rhinitis.

Feng Suoyi S Ju Longzhu L Shao Ziqi Z Grzanna Mark M Jia Lu L Liu Ming M

Journal of inflammation research 20200721

<h4>Objective and design</h4>Allergic rhinitis (AR) is an immunoglobulin E (IgE)-mediated inflammatory respiratory hypersensitivity characterized by elevated Th2 cytokines and infiltration of inflammatory cells to nasal tissues. BX471 is a small-molecule C-C chemokine receptor type 1 (CCR1) antagonist involved in suppression of inflammation via blocking of primary ligands. In this study, we examined the anti-inflammatory effect of BX471 on ovalbumin (OVA)-induced AR mice model.<h4>Materials and ...[more]

PMID: 32801828

Similar Datasets

Project description:BackgroundOral antihistamines that target the histamine receptor-1, such as fexofenadine, offer suboptimal relief of allergic rhinitis-associated nasal congestion. Combinations with oral sympathomimetics, such as pseudoephedrine, relieve congestion but produce side effects. Previous animal and human studies with histamine receptor-3 antagonists, such as PF-03654764, demonstrate promise.MethodsHerein we employ the Environmental Exposure Unit (EEU) to conduct the first randomized controlled trial of PF-03654764 in allergic rhinitis. 64 participants were randomized in a double-blind, placebo-controlled 4-period crossover study. Participants were exposed to ragweed pollen for 6 hours post-dose in the EEU. The primary objective was to compare the effect of PF-03654764 + fexofenadine to pseudoephedrine + fexofenadine on the subjective measures of congestion and Total Nasal Symptom Score (TNSS). The objectives of our post-hoc analyses were to compare all treatments to placebo and determine the onset of action (OA). This trial was registered at ClinicalTrials.gov (NCT01033396).ResultsPF-03654764 + fexofenadine was not superior to pseudoephedrine + fexofenadine. In post-hoc analyses, PF-03654764 + fexofenadine significantly reduced TNSS, relative to placebo, and OA was 60 minutes. Pseudoephedrine + fexofenadine significantly reduced congestion and TNSS, relative to placebo, with OA of 60 and 30 minutes, respectively. Although this study was not powered for a statistical analysis of safety, it was noted that all PF-03654764-treated groups experienced an elevated incidence of adverse events.ConclusionsPF-03654764 + fexofenadine failed to provide superior relief of allergic rhinitis-associated nasal symptoms upon exposure to ragweed pollen compared to fexofenadine + pseudoephedrine. However, in post-hoc analyses, PF-03654764 + fexofenadine improved TNSS compared to placebo. Side effects in the PF-03654764-treated groups were clinically significant compared to the controls.

Project description:Allergic rhinitis (AR) is a common chronic inflammatory disease of the upper respiratory tract. Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer and belongs to environmental endocrine disruptors (EDCs). It can be entered the human body which is harmful to health. The relationship between DEHP and AR is still inconclusive. This study aims to investigate the effect of environmental pollutants DEHP on AR. By examining DEHP metabolites in the urine of AR patients and building an AR model. 24 BALB/c mice were used as the study subjects, and ovalbumin (OVA) and DEHP (3 mg/kg/body) were used for intragastric administration. They were divided into control group, DEHP group, OVA group and OVA?+?DEHP group. Examination, behavioral scoring, inflammatory factor testing, oxidative stress testing, detection of aryl hydrocarbon receptor (AhR) and signaling pathways CYP1A1 and CYP1B1 related proteins and mRNA. The concentrations of 3 metabolites of DEHP (MEHHP, MEOHP, and MEHP) in urine of AR patients were higher. And HE-staining showed that for the control group, many chronic inflammatory cell infiltration and nasal mucosal destruction were observed in the OVA?+?DEHP group and were more severe than the OVA group. Allergic symptom scores were obtained from sneezing, scratching, number of scratching, and nose flow. The scores of the OVA group and the OVA?+?DEHP group were higher than 7 points. Serum ELISA and nasal mucosal oxidative stress tests are more serious in the OVA?+?DEHP group. The expression of AhR protein and its mRNA was increased in the DEHP group, OVA group and OVA?+?DEHP group. The OVA?+?DEHP group was more significant in the OVA group and DEHP group. And the mRNAs of the AhR-related signaling pathways CYP1A1 and CYP1B1 were also more prominent in the OVA?+?DEHP group. DEHP may aggravate its inflammatory response through the AhR pathway closely related to the environment. When combined with OVA, DEHP can further aggravate the OVA-induced nasal inflammatory response and make the nasal cavity have undergone severe changes, and many inflammatory cells have infiltrated. DEHP has shown an adjuvant effect, and the AhR-related signaling pathways CYP1A1 and CYP1B1 may be critical.

Dataset Information

Therapeutic Effect of C-C Chemokine Receptor Type 1 (CCR1) Antagonist BX471 on Allergic Rhinitis.

Publications

Therapeutic Effect of C-C Chemokine Receptor Type 1 (CCR1) Antagonist BX471 on Allergic Rhinitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets