Dataset Information

Phosphodiesterase 4 Inhibitors in Allergic Rhinitis/Rhinosinusitis.

ABSTRACT: Allergic rhinitis/rhinosinusitis (AR) is the most common allergic disease. It affects patients' quality of life and may influence the severity of lower airway disease such as asthma. Therefore, its treatment is of great importance. AR is treated by a combination of effective approaches; however, in some patients, the disease is uncontrolled. In the last several years, the concept of AR has shifted from increased T helper 2 (Th2) cell signaling and downstream inflammation to disease phenotypes with non-Th2-mediated inflammation. AR is a largely heterogenous group of airway diseases, and as such, research should not only focus on immunosuppressive agents (e.g., corticosteroids) but should also include targeted immunomodulatory pathways. Here, we provide an overview of novel therapies, focusing on the role of phosphodiesterase-4 (PDE4) inhibitors in AR. PDE4 inhibitors are potent anti-inflammatory agents that are used for the treatment of inflammatory airway diseases including AR. The PDE4 inhibitor roflumilast was shown to effectively control symptoms of AR in a randomized, placebo-controlled, double-blinded, crossover study in patients with a history of AR. However, only a few PDE4 inhibitors have proceeded to phase II and III clinical trials, due to insufficient clinical efficacy and adverse effects. Research is ongoing to develop more effective compounds with fewer side effects that target specific inflammatory pathways in disease pathogenesis and can provide more consistent benefit to patients with upper airway allergic diseases. Novel specific PDE4 inhibitors seem to fulfill these criteria.

SUBMITTER: Janosova V

PROVIDER: S-EPMC7387511 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Phosphodiesterase 4 Inhibitors in Allergic Rhinitis/Rhinosinusitis.

Janosova Viera V Calkovsky Vladimir V Pedan Heiko H Behanova Estera E Hajtman Andrej A Calkovska Andrea A

Frontiers in pharmacology 20200722

Allergic rhinitis/rhinosinusitis (AR) is the most common allergic disease. It affects patients' quality of life and may influence the severity of lower airway disease such as asthma. Therefore, its treatment is of great importance. AR is treated by a combination of effective approaches; however, in some patients, the disease is uncontrolled. In the last several years, the concept of AR has shifted from increased T helper 2 (Th2) cell signaling and downstream inflammation to disease phenotypes wi ...[more]

PMID: 32792957

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Project description:ObjectivesPrevious research has suggested connections between specific inflammatory cytokines and nasal conditions, including Allergic Rhinitis (AR), Chronic Rhinosinusitis (CRS), and Nasal Polyps (NP). However, a lack of robust research establishing the causal underpinnings of them. This Mendelian Randomization (MR) study aims to evaluate the causal relationships between 41 inflammatory cytokines and the incidence of AR, CRS and NP.MethodsThis study employed a two-sample MR design, harnessing genetic variations derived from publicly accessible genome-wide association studies (GWAS) datasets. AR data was sourced from a GWAS with 25,486 cases and 87,097 controls (identifier: ukb-b-7178). CRS data originated from a GWAS encompassing 1,179 cases and 360,015 controls (identifier: ukb-d-J32). NP data was extracted from a GWAS involving 1,637 cases and 335,562 controls (identifier: ukb-a-541). The data for 41 inflammatory cytokines were obtained from an independent GWAS encompassing 8,293 participants. Inverse variance weighted (IVW), MR Egger regression and Weighted median were used to evaluate the causalities of exposures and outcomes. A range of sensitivity analyses were implemented to assess the robustness of the results.ResultsThe results revealed significant associations between elevated circulating levels of MIP-1α (odds ratio, OR: 1.01798, 95% confidence interval, CI: 1.00217-1.03404, p = 0.02570) and TNF-α (OR: 1.01478, 95% CI: 1.00225-1.02746, p = 0.02067) with an augmented risk of AR in the IVW approach. Heightened levels of circulating IL-2 exhibited a positive correlation with an increased susceptibility to NP in the IVW approach (OR: 1.00129, 95% CI: 1.00017-1.00242, p = 0.02434), whereas elevated levels of circulating PDGF-BB demonstrated a decreased risk of NP (OR: 0.99920, 95% CI: 0.99841-0.99999, p = 0.047610). The MR analysis between levels of 41 inflammatory cytokines and the incidence of CRS yielded no positive outcomes.ConclusionThis investigation proposes a potential causal association between elevated levels of MIP-1α and TNF-α with an elevated risk of AR, as well as an increased risk of NP linked to elevated IL-2 levels. Furthermore, there appears to be a potential association between increased levels of circulating PDGF-BB and a reduced risk of NP.

Project description:IntroductionAlthough recent studies have shown that the human microbiome is involved in the pathogenesis of allergic diseases, the impact of microbiota on allergic rhinitis (AR) and non-allergic rhinitis (nAR) has not been elucidated. The aim of this study was to investigate the differences in the composition of the nasal flora in patients with AR and nAR and their role in the pathogenesis.MethodFrom February to September 2022, 35 AR patients and 35 nAR patients admitted to Harbin Medical University's Second Affiliated Hospital, as well as 20 healthy subjects who underwent physical examination during the same period, were subjected to 16SrDNA and metagenomic sequencing of nasal flora.ResultsThe microbiota composition of the three groups of study subjects differs significantly. The relative abundance of Vibrio vulnificus and Acinetobacter baumanni in the nasal cavity of AR patients was significantly higher when compared to nAR patients, while the relative abundance of Lactobacillus murinus, Lactobacillus iners, Proteobacteria, Pseudomonadales, and Escherichia coli was lower. In addition, Lactobacillus murinus and Lacttobacillus kunkeei were also negatively correlated with IgE, while Lacttobacillus kunkeei was positively correlated with age. The relative distribution of Faecalibacterium was higher in moderate than in severe AR patients. According to KEGG functional enrichment annotation, ICMT(protein-S-isoprenylcysteine O-methyltransferase,ICMT) is an AR microbiota-specific enzyme that plays a role, while glycan biosynthesis and metabolism are more active in AR microbiota. For AR, the model containing Parabacteroides goldstemii, Sutterella-SP-6FBBBBH3, Pseudoalteromonas luteoviolacea, Lachnospiraceae bacterium-615, and Bacteroides coprocola had the highest the area under the curve (AUC), which was 0.9733(95%CI:0.926-1.000) in the constructed random forest prediction model. The largest AUC for nAR is 0.984(95%CI:0.949-1.000) for the model containing Pseudomonas-SP-LTJR-52, Lachnospiraceae bacterium-615, Prevotella corporis, Anaerococcus vaginalis, and Roseburia inulinivorans.ConclusionIn conclusion, patients with AR and nAR had significantly different microbiota profiles compared to healthy controls. The results suggest that the nasal microbiota may play a key role in the pathogenesis and symptoms of AR and nAR, providing us with new ideas for the treatment of AR and nAR.

Dataset Information

Phosphodiesterase 4 Inhibitors in Allergic Rhinitis/Rhinosinusitis.

Publications

Phosphodiesterase 4 Inhibitors in Allergic Rhinitis/Rhinosinusitis.

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