Allergic Asthma Research Articles

NFATc1 in CD4+ T cells and CD11c+ dendritic cells drive Th2-mediated eosinophilic inflammation in allergic asthma

BackgroundAsthma, a chronic lung disease, is a significant public health problem worldwide. It is marked by increased Th2 response resulting in eosinophil accumulation. The pathophysiology of asthma involves various cell types, including epithelial cells, dendritic cells (DCs), innate lymphoid cells (ILCs), B cells, and effector cells. Nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a critical transcription factor for immune regulation, is known for its role in T cells and, more recently, in myeloid cells. However, the specific contributions of NFATc1 in T cells and DCs in the context of asthma are not well understood. ObjectiveExplore NFATc1’s role in T cells and dendritic cells in modulating Th2 immune responses within the pathophysiology of allergic asthma. MethodsMice lacking Nfatc1 in CD4+T cells or CD11c+ dendritic cells, were induced with asthma using house dust mite (HDM), enabling investigation into NFATc1's role in both cell types in experimental allergic asthma. Additionally, the study examined NFATc1 expression in these cells and its correlation with blood eosinophil levels in an adult asthma cohort. ResultsIn HDM-induced asthma model, we found that Nfatc1 deficiency either in CD4+ T cells or CD11c+ dendritic cells resulted in reduced Th2-driven eosinophilic inflammation, immunoglobulin E (IgE) levels, and mast cell presence in the lung of asthmatic mice. Nfatc1's absence in CD4+ T cells directly hampered Th2 cell polarization and functionality, whereas in CD11c+ dendritic cells, it affected DC differentiation and maturation, thereby weakening T cell priming, proliferation and subsequent Th2 differentiation. Correspondingly, translational research indicated significant correlations between CD4+NFATc1+ and CD11c+NFATc1+ cell populations and eosinophil levels in asthmatic patients, but not in healthy controls. ConclusionNFATc1 in T cells and dendritic cells modulate Th2-mediated eosinophilic inflammation in allergic asthma, which offering insights into asthma pathogenesis and identifying NFATc1 as a potential target for therapeutic intervention.

Sensitisation to Lep d 2- Lepidoglyphus destructor allergy in asthma and rhinitis.

Background. Mites are responsible for allergic diseases, such as asthma and rhinitis, in nearly 1.5% of the world population. It is known that nowadays, besides House Dust Mites (HDM), Storage Mites (SM) are important sensitisers in urban non-occupational dwellings, predominantly in the Mediterranean area. The main objective of our study was to analyse the clinical relevance of the most prevalent SM, Lepidoglyphus destructor, by assessing the relationship between sensitisation to the major molecular allergen Lep d 2 and allergic respiratory disease phenotype in an urban population monosensitised to this molecular allergen. Methods. Cross-sectional study which included consecutive patients evaluated in our Allergy Department between 2012 and 2018, from urban non-occupational setting, with rhinitis and/or asthma, perennial symptoms and proven sensitisation to SM Lep d 2, tested using ImmunoCAP Immuno Solid-phase Allergen Chip (ISAC) technology, which detects 112 allergens. Results. A total of 37 allergic patients were included (23 female), aged 20.1 ± 12.8, min-max 5-58 years-old. The molecular sensitisation profile showed 18.9% of L. destructor mite monosensitised patients, having only sIgE to Lep d 2. This subset of patients mainly had allergic rhinitis, with 28.6% also being asthmatic. Regarding severity, most patients showed a persistent moderate phenotype of respiratory disease. The mean value of Lep d 2 sIgE was 8.3 ± 9.8 ISU-E, lower than in mite polysensitised patients (21.7 ± 21.5, p = 0.049). Conclusions. Our proof-of-concept study focused on Lep d 2 monosensitisation, showed that SM may have clinical relevance in perennial allergic asthma and rhinitis, and should be taken into account when assessing and treating allergic respiratory disease. Conclusions. The present survey demonstrated that Italian primary care pediatricians accomplish ARIA guidelines and adapt treatment on the basis of the intensity of symptoms. Corticosteroids and antihistamines are the most common prescribed medications. Nasal lavages are also popular.

Local receptor-interacting protein kinase 2 inhibition mitigates house dust mite-induced asthma.

House dust mite is the most frequent trigger of allergic asthma, with innate and adaptive immune mechanisms playing critical roles in outcomes. We recently identified the nucleotide-binding oligomerisation domain 1 (NOD1)/receptor-interacting serine/threonine protein kinase 2 (RIPK2) signalling pathway as a relevant contributor to murine house dust mite-induced asthma. This study aimed to evaluate the effectiveness of a pharmacological RIPK2 inhibitor administered locally as a preventive and therapeutic approach using a house dust mite-induced asthma model in wild-type and humanised NOD1 mice harbouring an asthma-associated risk allele, and its relevance using air-liquid interface epithelial cultures from asthma patients. A RIPK2 inhibitor was administered intranasally either preventively or therapeutically in a murine house dust mite-induced asthma model. Airway hyperresponsiveness, bronchoalveolar lavage composition, cytokine/chemokine expression and mucus production were evaluated, as well as the effect of the inhibitor on precision-cut lung slices. Furthermore, the inhibitor was tested on air-liquid interface epithelial cultures from asthma patients and controls. While local preventive administration of the RIPK2 inhibitor reduced airway hyperresponsiveness, eosinophilia, mucus production, T-helper type 2 cytokines and interleukin 33 (IL-33) in wild-type mice, its therapeutic administration failed to reduce the above parameters, except IL-33. By contrast, therapeutic RIPK2 inhibition mitigated all asthma features in humanised NOD1 mice. Results in precision-cut lung slices emphasised an early role of thymic stromal lymphopoietin and IL-33 in the NOD1-dependent response to house dust mite, and a late effect of NOD1 signalling on IL-13 effector response. RIPK2 inhibitor downregulated thymic stromal lymphopoietin and chemokines in house dust mite-stimulated epithelial cultures from asthma patients. These data support that local interference of the NOD1 signalling pathway through RIPK2 inhibition may represent a new therapeutic approach in house dust mite-induced asthma.

CD226 implicated in Akt-dependent apoptosis of CD4+ T cell contributes to asthmatic pathogenesis.

Asthma is a chronic airway inflammatory disease in which CD4+ T cell dysregulation occurs. Here, we investigated the molecular role and clinical significance of CD226, a costimulatory molecule of T lymphocytes, in the development of allergic asthma. Our results revealed that the expression of CD226 was significantly increased in CD4+ effector T cells, especially in T helper (Th) 2 cells and Th17 cells in patients with asthma. Moreover, CD4+ T cell-specific Cd226-knockout mice were generated and together with littermates were challenged with ovalbumin (OVA) to establish a model of allergic asthma. We found that CD226 deficiency in CD4+ T cells mitigated lung inflammation, IgE production, and eosinophil infiltration and reduced airway remodeling in experimental allergic asthma. However, the impact of CD226 on asthma was independent of Treg cell modulation. Through RNA-seq data analysis, the apoptosis pathway was screened. Mechanistically, CD226 deletion promoted CD4+ T cell late apoptosis via the activation of Caspase-3 in an Akt-dependent manner. Furthermore, blocking CD226 signaling with a recombinant fusion protein attenuated asthma features in mice and achieved a good therapeutic effect. Overall, this study revealed a unique role of CD226 in CD4+ T cell regulation in asthma pathogenesis. Therefore, targeting CD226 may provide new insights into the clinical treatment of asthma.

Association between Type of Tobacco Use and Allergic Rhinitis and Bronchial Asthma in Adults

Association between Type of Tobacco Use and Allergic Rhinitis and Bronchial Asthma in Adults

Interleukin 9 mediates T follicular helper cell activation to promote antibody responses.

Antigen-specific humoral responses are orchestrated through complex interactions among immune cells in lymphoid tissues, including the collaboration between B cells and T follicular helper (Tfh) cells. Accumulating evidence indicates a crucial role for interleukin-9 (IL-9) in the formation of germinal centers (GCs), enhancing the generation of class-switched high-affinity antibodies. However, the exact function of IL-9 in Tfh cell regulation remains unclear. In this study, we examined the humoral immune responses of CD4Cre/+Il9rafl/fl mice, which lack an IL-9-specific receptor in Tfh cells. Upon intraperitoneal immunization with sheep red blood cells (SRBCs), CD4Cre/+Il9rafl/fl mice displayed diminished levels of SRBC-specific IgG antibodies in their sera, along with reduced levels of GC B cells and plasma cells. Notably, Il9ra-deficient Tfh cells in the spleen exhibited decreased expression of their signature molecules such as B-cell lymphoma 6, C-X-C chemokine receptor 5, IL-4, and IL-21 compared to control mice. In models of allergic asthma induced by house dust mite (HDM) inhalation, CD4Cre/+Il9rafl/fl mice failed to elevate serum levels of HDM-specific IgE and IgG. This was accompanied by reductions in Tfh cells, GC B cells, and plasma cells in mediastinal lymph nodes. Furthermore, group 2 innate lymphoid cells (ILC2s) were identified as producers of IL-9 under immunizing conditions, possibly induced by leukotrienes released by activated IgD+ B cells around the T-B border. These observations may indicate the critical role of IL-9 receptor signaling in the activation of Tfh cells, with ILC2s potentially capable of supplying IL-9 in organized lymphoid tissues.

Exploring exhaled breath volatile organic compounds in occupational asthma: a pilot cross-sectional study

Occupational asthma (OA) is divided into allergic asthma (AA) and irritant-induced asthma (IIA). IIA can be divided further into three different phenotypic subtypes. Volatile organic compounds (VOCs) in exhaled breath can reflect metabolic changes in the body, and a wide range of them have been associated with various diseases in the last two decades. This is the first known study to explore breath VOCs in subjects with OA, aimed to identify potential biomarkers to distinguish OA from healthy controls, as well as between different OA subgroups. In a cross-sectional investigation, exhaled breath from 40 patients with OA and 45 respiratory healthy healthcare workers were collected with ReCIVA® Breath Sampler. Samples were analyzed through an untargeted approach using thermal desorption-gas chromatography mass spectrometry (TD-GC-MS), and VOCs were identified according to tier classification. The data underwent analysis using both non-parametric and parametric statistical methods. 536 VOCs were identified. Significance (p<0.05) was observed in several emitted VOCs. Among these, compounds such as 1-hexadecanol, 2,3-butanediol, xylene, phenol, acetone, 3-methylhexane, methylcyclohexane, and isoprene have biological implications or are associated with exposures linked to OA. These VOCs may reflect metabolic changes in the body and the microbiome, as well as external exposures due to occupation.&#xD;In particular, 1-hexadecanol, 2,3-butanediol, xylene and phenol are associated with reduced nicotinamide adenine dinucleotide (NADH) and production of reactive oxygen species (ROS), mechanisms that can be linked to asthmatic diseases and therefore suggests its potential as biomarkers. This study demonstrates that VOCs detected in exhaled breath could serve as indicators of occupational exposure and enhance diagnostic accuracy for asthma.&#xD.

Ayurveda Management of Allergic Rhinitis: Protocol for a Randomized Controlled Trial.

Allergic rhinitis (AR) is the inflammation of the membranes lining the nose due to allergen exposure and is characterized by sneezing, nasal congestion, itching of the nose, or postnasal discharge. The prevalence varies worldwide, perhaps due to the geographic and aeroallergen differences, with 10% to 30% of the world's population experiencing AR. In this study, Anu Taila Nasya, Naradiya Laxmivilas Rasa, and Shirishadi Kwath will be compared to a fluticasone nasal spray. The primary aim is to assess the efficacy of Ayurvedic management for AR (or vataja pratishyaya) by comparing it to a conventional control group. The secondary aims are to determine the mean change in the nasal endoscopy index and the mean change in the laboratory tests. This ongoing study is an open-label randomized controlled interventional trial, with a sample size of 90 both in the trial and standard control group (including dropouts, 20%), and will be carried out for 24 months. Participants in the trial group will receive Ayurvedic treatment, that is, Anu Taila Nasya (6 drops in each nostril for 7 days for 3 consecutive weeks), Naradiya Laxmivilas Rasa (250 mg twice per day), and Shirishadi Kwath (40 ml twice per day for 45 days). The participants in the control group will receive a fluticasone propionate nasal spray (2 sprays once per day for 45 days). The primary outcome will include the mean change in the Control of Allergic Rhinitis and Asthma Test score, and the secondary outcomes will include the mean change in the nasal endoscopy index (assessment of nasal membrane color, pale or hyperemia; rhinorrhea, watery or yellow; and inferior turbinate swelling, hypertrophy) and the mean change in the laboratory tests. As of May 2024, 72 patients have been enrolled in both groups. Data analysis should be completed by February 2025. The study will be reported following standard guidelines for reporting randomized controlled trials. Clinical results will be disseminated through conferences and peer-reviewed publication in a relevant journal. The Ayurvedic approach could be an evidence-based therapeutic tactic for the management of AR. Clinical Trials Registry India CTRI/2023/06/053395; https://tinyurl.com/564d2zz8. DERR1-10.2196/56063.

Exploring CD26-/lo subpopulations of lymphocytes in asthma phenotype and severity: A novel CD4+ T cell subset expressing archetypical granulocyte proteins.

Asthma pathology may induce changes in naïve/memory lymphocyte proportions assessable through the evaluation of surface CD26 (dipeptidyl peptidase 4/DPP4) levels. Our aim was to investigate the association of asthma phenotype/severity with the relative frequency of CD26-/lo, CD26int and CD26hi subsets within different lymphocyte populations. The proportion of CD26-/lo, CD26int and CD26hi subsets within CD4+ effector T cells (Teff), total CD4- lymphocytes, γδ-T cells, NK cells and NKT cells was measured in peripheral blood samples from healthy (N = 30) and asthma (N = 119) donors with different phenotypes/severities by flow cytometry. We performed K-means clustering analysis and further characterised the CD4+CD26-/lo Teff cell subset by LC-MS/MS and immunofluorescence. Cluster analysis including clinical and flow cytometry data resulted in four groups, two of them with opposite inflammatory profiles (neutrophilic vs. eosinophilic). Neutrophilic asthma presented reduced CD4-CD26hi cells, which negatively correlated with systemic inflammation. Eosinophilic asthma displayed a general expansion of CD26-/lo subsets. Specifically, CD4+CD26-/lo Teff expansion was confirmed in asthma, especially in atopic patients. Proteomic characterisation of this subset with a TEM/TEMRA phenotype revealed upregulated levels of innate (e.g. MPO and RNASE2) and cytoskeleton/extracellular matrix (e.g. MMP9 and ACTN1) proteins. Immunofluorescence assays confirmed the presence of atypical proteins for CD4+ T cells, and an enrichment in 'flower-like' nuclei and MMP9/RNASE2 levels in CD4+CD26-/lo Teff compared to CD4+ T lymphocytes. There is an association between CD26 levels in different lymphocyte subsets and asthma phenotype/severity. CD4+CD26-/loTEMRA cells expressing innate proteins specific to eosinophils/neutrophils could be determinant in sustaining long-term inflammation in adult allergic asthma.

Low CD46 expression on activated CD4+ T cells predict improved Th1 cell reactivity to calcitriol in majority of patients with allergic eosinophilic asthma and healthy donors.

Previous research showed that the intracellular complement system, with CD46 as its central molecule, regulates the Th1 response associated with IFN-γ production and transition to a type 1 regulatory response (Tr1) characterized by IL-10 production. This transition can be influenced by a vitamin D (calcitriol), favouring a shift towards Tr1 cells and increased IL-10 production, as described in some autoimmune diseases. It is unknown whether calcitriol modulates CD46-induced Th1 response towards regulatory type 1 T cells (Tr1) in allergic eosinophilic asthma and its value in relation to reducing inflammatory response. CD4+ T cells from 58 patients with allergic eosinophilic asthma (AEA) and 49 healthy donors (HDs) were stimulated with αCD3/αCD46/IL-2 or αCD3/αCD46/IL-2/Calcitriol in vitro for 60 h and analyzed by flow cytometry. IFN-γ and IL-10 levels in cell culture supernatants were measured using ELISA. CD4+ T cells from patients with AEA demonstrated elevated CD46 expression in both the non-activated state and under stimulation conditions with αCD3/αCD46/IL-2 or αCD3/αCD46/IL-2/Calcitriol. Moreover, CD46 expression in AEA patients fluctuated with the pollen season, showing a significant increase during period of low pollen exposure. Calcitriol further induced CD4+Tr1 cells from in vitro generated CD4+Th1 cells in both HDs and AEA patients. However, in both cohorts were individuals (HDs: 35/49, AEA: 40/58) who responded to calcitriol with a more pronounced regulatory response. The calcitriol-induced regulatory effect manifested by a stronger surface decrease of CD46 on activated CD4+ T cells (by 40% in HDs and by 26% in AEA), accompanied by a significant inhibition of IFN-γ and increased IL-10 production (by 31% in HDs and by 85% in AEA). These individuals were termed as the CD46D group. Contrary to this, calcitriol induced an increase in CD46 expression at the CD4+ T cell surface in a minor group of HDs (14/49), and AEA patients (18/58), who were termed as the CD46I group. In CD46I group, CD4+ T cells produced less IFN-γ in comparison with CD46D group (by 33% in HDs and by 43% in AEA) and were unable to upregulate IL-10 production following stimulation with αCD3/αCD46/IL-2/Calcitriol. Our results suggest the potential existence of a key for stratifying individuals suitable for calcitriol treatment in the context of low serum vitamin D levels. After validation in clinical studies, this key could be used as an adjunctive therapy not only for patients with allergic eosinophilic asthma, but also for other diseases.

Schisandrol A Alleviates Allergic Asthma in Mice via Regulating the NF-κB/IκBα and Nrf2/HO-1 Signaling Pathways.

Schisandra chinensis (Turcz) Baill (S. chinensis) is the key traditional Chinese medicine for the treatment of asthma used by ancient and modern medical practitioners. However, the material basis and the main mechanism of its antiasthmatic effect remain unclear. Our preliminary results showed that schisandrol A (SCA), a representative monomer of Schisandra lignans, had the best relaxation effect on tracheal rings in isolated rats. In this research, a mouse asthma model was prepared by combining ovalbumin (OVA) with Al (OH)3 for exploring the antiasthmatic action and the underlying mechanism of SCA. The study results demonstrated that SCA improved the behavior of mice with asthma and pathological changes in their lung tissues and airways, decreased serum immunoglobulin E (IgE) and OVA-IgE levels, interleukin-4 (IL-4), IL-5, IL-13, and eotaxin contents, and leukocytes number in bronchoalveolar lavage fluid. SCA downregulated the gene expressions of keratinocyte-derived protein chemokines and ILs and reduced the expressions of phosphorylated IκB kinase α (p-IKKα) and p-nuclear factor kappa-B (NF-κB) proteins in lung tissues. In addition, it was found that SCA could significantly increase T-superoxide dismutase and catalase activities, decrease malondialdehyde content, and elevate p-IκBα, NF-E2-related-factor 2 (Nrf2), and heme oxygenase-1 (HO-1) protein expressions. In summary, SCA treatment resulted in a significant improvement in the allergic bronchial asthma in mice, and its mechanisms may involve the regulation of the NF-κB/IκBα pathway to reduce inflammatory response and the Nrf2/HO-1 pathway to improve the body's antioxidant capacity. These results suggest that SCA is a key component of S. chinensis in exerting antiasthmatic effects.

Genetic correlation between chronic sinusitis and autoimmune diseases.

The association between autoimmune diseases and chronic rhinosinusitis in observational studies remains unclear. This study aimed to explore the genetic correlation between chronic rhinosinusitis and autoimmune diseases. We employed Mendelian randomization (MR) analysis and linkage disequilibrium score regression (LDSC) to investigate causal relationships and genetic correlations between autoimmune phenotypes and chronic rhinosinusitis. Additionally, transcriptome-wide association (TWAS) analysis was conducted to identify the shared genes between the two conditions to demonstrate their relationship. The CRS GWAS (genome-wide association study) data and other autoimmune diseases were retrieved from ieuOpenGWAS (https://gwas.mrcieu.ac.uk/), the FinnGen alliance (https://r8.finngen.fi/), the UK Biobank (https://www.ukbiobank.ac.uk/), and the EBI database (https://www.ebi.ac.uk/). Utilizing a bivariate two-sample Mendelian randomization approach, our findings suggest a significant association of chronic rhinosinusitis with various autoimmune diseases, including allergic rhinitis (p = 9.55E-10, Odds Ratio [OR] = 2,711.019, 95% confidence interval [CI] = 261.83391-28,069.8), asthma (p = 1.81E-23, OR = 33.99643, 95%CI = 17.52439-65.95137), rheumatoid arthritis (p = 9.55E-10, OR = 1.115526, 95%CI = 1.0799484-1.1522758), hypothyroidism (p = 2.08828E-2, OR = 4.849254, 95%CI = 1.7154455-13.707962), and type 1 diabetes (p = 2.08828E-2, OR = 01.04849, 95%CI = 1.0162932-1.0817062). LDSC analysis revealed a genetic correlation between the positive autoimmune phenotypes mentioned above and chronic rhinosinusitis: AR (rg = 0.344724754, p = 3.94E-8), asthma (rg = 0.43703672, p = 1.86E-10), rheumatoid arthritis (rg = 0.27834931, p = 3.5376E-2), and hypothyroidism (rg = -0.213201473, p = 3.83093E-4). Utilizing the Transcriptome-Wide Association Studies (TWAS) approach, we identified several genes commonly associated with both chronic rhinosinusitis and autoimmune diseases. Genes such as TSLP/WDR36 (Chromosome 5, top SNP: rs1837253), ORMDL3 (Chromosome 13, top SNP: rs11557467), and IL1RL1/IL18R1 (Chromosome 2, top SNP: rs12905) exhibited a higher degree of consistency in their shared involvement across atopic dermatitis (AT), allergic rhinitis (AR), and chronic rhinosinusitis (CRS). Current evidence suggests a genetic correlation between chronic rhinosinusitis and autoimmune diseases like allergic rhinitis, asthma, rheumatoid arthritis, hypothyroidism, and type 1 diabetes. Further research is required to elucidate the mechanisms underlying these associations.

High burden of respiratory allergy in children warrants early identification and treatment with allergen immunotherapy

Respiratory allergy often begins in childhood and most commonly manifests as allergic rhinitis (upper airways) and/or asthma (lower airways). Children with upper respiratory allergy often suffer from coexisting asthma, and other comorbidities ranging from gastrointestinal disorders to emotional/mental health disorders. Consequently, the disease burden is considerable and profoundly impacts a child's daily life.Early identification and appropriate management are important to reduce disease burden, lower the risk of disease progression and additional comorbidities, and protect the child's future well-being. A window of opportunity for halting disease progression may open in the early stages of allergic disease and underlines the importance of early diagnosis and treatment of children at risk. This review offers advice on identifying children with a high disease burden who would benefit from early intervention.Allergen immunotherapy (AIT) modifies the cause of respiratory allergy and prevents disease progression. In clinical practice, AIT could be considered as an early treatment for eligible children, to achieve long-term symptom control and disease modification.

Expression of Semaphorin3E/PlexinD1 in Human airway smooth muscle cells of COPD patients.

Semaphorin-3E (sema3E) is a member of axon guidance proteins that have emerged recently as essential regulators of cell migration and proliferation. It binds to plexinD1 with high affinity and is expressed in different cell types, including immune, cancer, and epithelial cells. Recent work in our lab has revealed a critical immunoregulatory role of sema3E in experimental allergic asthma; however, its role in COPD remains unclear. This study aimed to investigate the expression of sema3E and its receptor, plexinD1, in the airways of COPD patients and whether sema3E regulates airway smooth muscle (ASM) cell proliferation, a key feature of airway remodelling in COPD. We first demonstrate that human ASM cells obtained from COPD express sema3E and plexinD1 at both mRNA and protein levels. Also, bronchial sections from COPD patients displayed immunoreactivity of sema3E and its receptor plexinD1, suggestive of functional contribution of sema3E in airway remodeling. In contrast to ASM cells from healthy donors, sema3E did not inhibit the platelet-derived growth factor (PDGF) induced cell proliferation in ASM cells of COPD patients that were consistent with the binding of endogenous sema3E to its receptors on the cell surface and the expression and release of p61KDa-sema3E isoform. Our results support the sema3E-plexinD1 axis involvement in COPD airway smooth muscle remodelling.

Discovering potential asthma therapeutics targeting hematopoietic prostaglandin D2 synthase: An integrated computational approach

Allergic asthma, a chronic inflammatory illness that affects millions worldwide, has serious economic and health consequences. Despite advances in therapy, contemporary treatments have poor efficacy and negative effects. This study investigates hematopoietic prostaglandin D2 synthase (HPGDS) as a potential target for novel asthma therapies. Targeting HPGDS may provide innovative treatment methods. A library of phytochemicals was used to find putative HPGDS inhibitors by structure-based and ligand-based virtual screening. Among the 2295 compounds screened, four compounds (ZINC208828240, ZINC95627530, ZINC14727536, and ZINC14711790) demonstrated strong binding affinities of −10.4, −10.3, −9.2, −9.1 kcal/mol respectively with key residues, suggesting their potential as a highly effective HPGDS inhibitor. Molecular dynamics (MD) simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) computations were further performed to evaluate the stability and binding affinity of the complexes. MD simulations and MMPBSA confirmed that compound ZINC14711790 showed high stability and binding affinity (binding energy −31.52 kcal/mol) than other compounds, including HQL-79, suggesting that this compound might be used as promising inhibitors to treat asthma. RMSD and RMSF analysis also revealed that ZINC14711790 exhibited strong dynamic stability. The findings of this study show the efficacy of ZINC14711790 as HPGDS inhibitors with high binding affinity, dynamic stability, and appropriate ADMET profile.

Baicalin Attenuates Type 2 Immune Responses in a Mouse Allergic Asthma Model through Inhibiting the Production of Thymic Stromal Lymphopoietin

Plain Language SummaryBaicalin is a flavonoid chemical extracted and purified from Scutellaria baicalensis Georgi, which possesses broad pharmacological properties. Our work objected to explore the protective effect of baicalin on allergic asthma and the possible mechanisms on regulating type 2 immune response. Mice were stimulated with OVA and administrated with baicalin. We found that eosinophils infiltrate in BALF were reduced remarkably in baicalin-treated asthmatic mice. Baicalin decreased OVA-induced inflammatory cytokines and serum immunoglobulin E secretion significantly. Moreover, baicalin alleviated the asthmatic pathological changes and substantially suppressed TSLP expression in the lung tissues. Our study indicates that baicalin attenuates OVA-induced allergic asthma in mice effectively by suppressing type 2 immune responses, which may provide a new mechanistic insight into the anti-asthmatic activity of baicalin.

MiR-146a-5p engineered hucMSC-derived extracellular vesicles attenuate Dermatophagoides farinae-induced allergic airway epithelial cell inflammation.

Allergic asthma is prevalent in children, with Dermatophagoides farinae as a common indoor allergen. Current treatments for allergic airway inflammation are limited and carry risks. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show promise as a cell-free therapeutic approach. However, the use of engineered MSC-EVs for D. farinae-induced allergic airway epithelial cell inflammation remains unexplored. We generated miR-146a-5p-engineered EVs from human umbilical cord mesenchymal stem cells (hucMSCs) and established D. farinae-induced mouse and human bronchial epithelial cell allergic models. Levels of IL-1β, IL-18, IL-4, IL-5, IL-6, IL-10, IL-33, TNF-α and IgE were detected using ELISA. The relative TRAF6 and IRAK1 mRNA expression was quantified using qPCR assay and the NLRP3, NF-κB, IRAK1 and TRAF6 protein expression was determined using Western blotting. The regulatory effect of IRAK1 and TRAF6 by miR-146a-5p was examined using a dual luciferase reporter assay, and the nuclear translocation of NF-κB p65 into 16-HBE cells was evaluated using immunofluorescence assay. Treatment with hucMSC-EVs effectively reduced allergic inflammation, while miR-146a-5p engineered hucMSC-EVs showed greater efficacy. The enhanced efficacy in alleviating allergic airway inflammation was attributed to the downregulation of IRAK1 and TRAF6 expression, facilitated by miR-146a-5p. This downregulation subsequently led to a decrease in NF-κB nuclear translocation, which in turn resulted in reduced activation of the NLRP3 inflammasome and diminished production of inflammatory cytokines, including IL-6, TNF-α, IL-1β and IL-18. Our study underscores the potential of miR-146a-5p engineered hucMSC-EVs as a cell-free therapeutic strategy for D. farinae-induced allergic airway inflammation, offering a promising avenue for boosting anti-inflammatory responses.

MicroED Structures of Fluticasone Furoate and Fluticasone Propionate Provide New Insights to Their Function.

The detailed understanding of fluticasone, a widely prescribed medicine for allergic rhinitis, asthma, and chronic obstructive pulmonary disease (COPD), has not been complete due to challenges in structural elucidation. The three-dimensional (3D) structure of fluticasone furoate 1 remained undetermined for decades, while the existing structures of fluticasone propionate 2 required refinement against improved data. In this study, we applied microcrystal electron diffraction (MicroED) to determine the 3D structures of 1 and 2 in their drug formulation state. Density functional theory (DFT) calculations were utilized to model solvent effects to determine the preferred geometries in solution. A comparative analysis of structures of 1 and 2 across three states (drug formulation state, in solution, and biologically active state) revealed major conformational changes during the entire transition. Potential energy plots were calculated for the most dynamic bonds, uncovering their rotational barriers. This study underscores the combined use of MicroED and DFT calculations to provide a comprehensive understanding of conformational and energy changes during drug functioning in humans. The quantitative comparison highlights the subtle structural differences that can lead to significant functional changes in pharmaceutical properties.

Different allergen-induced asthma and anaphylaxis show distinctive IgE pathway dependence

BackgroundThe pathogenesis of allergic asthma is classically understood to involve allergens crosslinking Immunoglobulin E (IgE) bound to mast cells, leading to the release of histamine and other inflammatory mediators. ObjectiveThis study aims to explore whether different allergens have distinct IgE-dependent mechanisms in mouse models of both asthma and anaphylaxis. MethodsWild type (WT) and IgE knockout (IgE KO) mice were used to generate asthma mouse models. Lung inflammation was assessed by histological analysis and inflammatory cells in Bronchial Alveolar Lavage Fluids (BALF). Passive Cutaneous Anaphylaxis (PCA) was conducted to quantify IgE, and Toluidine Blue staining was used to visualize mast cell recruitment. ResultsAll allergen-treated mice exhibited significant airway inflammation. Compared to WT mice, HDM-treated IgE KO mice showed an attenuated inflammatory profile, particularly with reduced eosinophils. These mice had lower serum levels of HDM-specific IgE and IgG1 as well as reduced levels of Th2 cytokines interleukin 4 (IL-4) and IL-5 in BALF. CRE-treated IgE KO mice also displayed a reduced inflammation, with significant differences only in eosinophils. Interestingly, no significant differences in airway inflammation were observed between OVA-treated IgE KO mice and WT mice. Furthermore, both HDM and CRE-induced PCA model showed significantly less Evan's blue dye leakage and mast cell recruitment in the ears of IgE KO mice compared to WT mice, with no differences for OVA-induced PCA and mast cell recruitment. ConclusionThe results highlight the variability in IgE pathway dependence among different allergens, emphasizing the need for further research to delineate the underlying mechanisms.

Cost-effectiveness of allergen immunotherapy.

Allergic rhinitis is a relevant and global health problem affecting up to 5-50% of the general population and its prevalence is increasing due to climate change and pollution among other factors and counts among the 10 most frequent reasons for medical consultation, generating an important economic impact. Allergen immunotherapy (AIT) is the only allergy-disease-modifying treatment and there is plenty of evidence of its effectiveness with regards subcutaneous and oral routes of AIT.This narrative review article examines published literature in the last 24 months regarding the pharmacoeconomics of AIT versus standard of care treatment (SOC) for the treatment of allergic rhinitis and asthma. Farraia et al. assessed in 2022 subcutaneous immunotherapy (SCIT, _438/$500.28) and sublingual immunotherapy (SLIT) (_1021/$1116.19) plus symptomatic treatment versus SOC treatment in children with HDM-driven allergic asthma, measuring QALYs, decrease of medication, decrease of exacerbations and symptoms. They used the cost-effective threshold: _18 482.80 ($21 110.14), finding that AIT is cost-effective.Also, SCIT and SLIT plus symptomatic treatment was assessed versus SOC treatment in children with grass pollen allergic rhinitis. The authors concluded that SCIT (_933/$1065.67) and SLIT (_1408/ $1608.22) seem cost-effective, particularly SCIT. Allergen immunotherapy is cost-effective in the management of allergic rhinitis and asthma as compared with SOC alone. As most studies consider only during-treatment costs and no long-term benefits or preventive effects are being assessed, the real cost-effectiveness of allergen immunotherapy could be even higher.