Mechanisms of exacerbation of Th2-mediated eosinophilic allergic asthma induced by plastic pollution derivatives (PPD): A molecular toxicological study involving lung cell ferroptosis and metabolomics.

Polystyrene microplastics (PS-MP) and dibutyl phthalate (DBP) are plastic pollution derivatives (PPDs) commonly found in the natural environment. To investigate the effects of PPD exposure on the risk of allergic asthma, we established a PPD exposure group in a mouse model. The dose administered for PS-MP was 0.1 mg/d and for DBP was 30 mg/kg/d, with a 5-week oral administration period. The pathological changes of airway tissue and the increase of oxidative stress and inflammatory response confirmed that PPD aggravated eosinophilic allergic asthma in mice. The mitochondrial morphological changes and metabolomics of mice confirmed that ferrotosis and oxidative stress played key roles in this process. Treatment with 100 mg/Kg deferoxamine (DFO) provided significant relief, and metabolomic analysis of lung tissue supported the molecular toxicological. Our findings suggest that the increased levels of reactive oxygen species (ROS) in the lungs lead to Th2-mediated eosinophilic inflammation, characterized by elevated IL-4, IL-5, and eosinophils, and reduced INF-γ levels. This inflammatory response is mediated by the NFκB pathway and exacerbates type I hypersensitivity through increased IL-4 production. In this study, the molecular mechanism by which PPD aggravates asthma in mice was elucidated, which helps to improve the understanding of the health effects of PPD and lays a theoretical foundation for addressing the health risks posed by PPD.

House dust mite immunotherapy: A real-world, prescription data-based analysis.

BACKGROUND: House dust mite (HDM) sensitisation can contribute to the development of allergic rhinoconjunctivitis (AR) or allergic asthma (AA). As treatment, allergen immunotherapy (AIT) is a promising approach, since it aims building immunotolerance against allergens, therewith establishing long-term efficacy. The evaluation of AIT has been investigated in many randomised controlled trials, whereas few real-world evidence studies are available. METHODS: We used data from the longitudinal prescription data base IQVIA™ LRx. Data on initial AIT prescriptions against HDM from January 2009 to December 2013 was analysed regarding treatment (subcutaneous AIT with either depigmented polymerised allergen extract [dSCIT] or other allergens [oSCIT], or sublingual immunotherapy [SLIT]) and treatment duration. Treatment groups were compared with a control group of AR patients not receiving AIT. Data on symptomatic medication was collected until February 2017 and progression of AR and AA was compared. RESULTS: Data of 7260 patients with AIT prescriptions and of 21,780 control patients was analysed. AIT was associated with a significant decrease of AR medication intake compared with control (dSCIT: -34.0%, p < 0.0001; oSCIT: -25.7%, p < 0.0001; SLIT: -37.7%, p = 0.0026). In asthmatics, SCIT was associated with a significant decrease of asthma medication compared with control (dSCIT: -45.2%, p < 0.0001; oSCIT: -32.9%, p < 0.0001). Further, a significantly reduced likelihood for onset of asthma medication was demonstrated in patients treated with SCIT compared with controls (dSCIT OR: 0.759, p = 0.0476; oSCIT OR: 0.815, p = 0.0339). CONCLUSION: Real-world data analyses indicate that AIT, particularly given via a subcutaneous route, reduces the need of medication against AR and AA and might delay the onset of asthma medication in patients with AR.

YiQi GuBen formula alleviates airway inflammation and airway remodeling in OVA-induced asthma mice through TLR4/NF-κB signaling pathway.

BACKGROUND: We aim to investigate the effect of YiQi GuBen formula (YQGB) on airway inflammation and airway remodeling in the ovalbumin (OVA)-induced asthma model to further explore the potential mechanisms of YQGB in treating allergic asthma. METHODS: Mice were divided into five groups randomly (n = 10): the control group, OVA group, OVA + Dex (0.1 mg/kg) group, OVA + low-dose (1.1 g/kg) YQGB group, and OVA + high-dose (2.2 g/kg) YQGB group. Inflammatory cell count and IgE were detected in bronchoalveolar lavage fluid (BALF). Lung tissue histopathology was observed by using H&E, PAS, Masson, and immunohistochemistry staining. qRT-PCR and western blot were applied to analyze key genes and proteins associated with TLR4 and NF-κB signaling pathways. RESULTS: In OVA-induced asthma mice, YQGB decreased eosinophils and IgE in BALF. YQGB alleviated the OVA-induced inflammatory infiltration and declined IL-4, IL-5, IL-13, Eotaxin, ECP, GM-CSF, LTC4, and LTD4. YQGB attenuated the OVA-induced goblet cell metaplasia and mucus hypersecretion. YQGB mitigated the OVA-induced subepithelial fibrosis and lowered TGF-ß1, E-Cadherin, Vimentin, and Fibronectin. YQGB ameliorated the OVA-induced airway smooth muscle thickening and lessened α-SMA and PDGF levels. YQGB reduced the expression of TLR4, MyD88, TRAF6, IκBα, and p65 mRNAs, and IκBα and p-p65 protein levels were also reduced. CONCLUSION: YQGB exhibits the anti-asthma effect by reducing airway inflammation and airway remodeling through suppressing TLR4/NF-κB signaling pathway, and is worth promoting clinically.

Evaluation and Comparison of the Efficacy of Subcutaneous and Sublingual Immunotherapy for the Treatment of Allergic Asthma in Children.

Specific immunotherapy represents the only potentially curative treatment for allergic asthma. Allergens can be administered subcutaneously (SCIT) or sublingually (SLIT). The aim of the current study was to evaluate and compare the efficacy of SCIT and SLIT for the treatment of allergic asthma in children. Our study included 69 children with allergic asthma who underwent immunotherapy for house dust mites or pollen for at least 3 consecutive years. After 3 years of SCIT and SLIT, the median number of asthma exacerbations in the last three months decreased from 2 to 0 (p < 0.01) and from 1 to 0 (p < 0.01), respectively. When comparing the efficacy of SCIT and SLIT, our study revealed a significantly better efficacy of SCIT only in terms of increasing lung function. The median increase in forced expiratory volume in one second (FEV1) after 3 years was 8% with SCIT and -1% with SLIT (p < 0.01). Daily controller therapy could be withdrawn or reduced in 9 out of 16 (56.3%) children who received it before SCIT (p < 0.01) and in 19 of 29 (65.6%) children who received it before SLIT (p < 0.01), but the difference in efficacy was not significant (p = 0.88). Both SCIT and SLIT are effective treatments for allergic asthma in children.

IL-37 protects against house dust mite-induced airway inflammation and airway epithelial barrier dysfunction via inhibiting store-operated calcium entry.

BACKGROUND: Airway epithelial barrier dysfunction has been proved to contribute to the development of type 2 inflammation of asthma. Interleukin (IL)-37 is a negative regulator of immune responses and allergic airway inflammation. However, whether IL-37 has any effect on airway epithelial barrier has been unknown. METHODS: We evaluated the role of IL-37 in both mouse model and cultured 16HBE cells. Histology and ELISA assays were used to evaluate airway inflammation. FITC-dextran permeability assay was used to evaluate the airway epithelial barrier function. Immunofluorescence, western blot and quantitative Real-Time PCR (RT-PCR) were used to evaluate the distribution and expression of tight junction proteins. RT-PCR and Ca2+ fluorescence measurement were used to evaluate the mRNA expression and activity of store-operated calcium entry (SOCE). RESULTS: IL-37 inhibited house dust mite (HDM)-induced airway inflammation and decreased the levels of IgE in serum and type 2 cytokines in bronchoalveolar lavage fluid (BALF) compared to asthmatic mice. IL-37 protected against HDM-induced airway epithelial barrier dysfunction, including reduced leakage of FITC-dextran, enhanced expression of TJ proteins, and restored the membrane distribution of TJ proteins. Moreover, IL-37 decreased the level of IL-33 in the BALF of asthmatic mice and the supernatants of HDM-treated 16HBE cells. IL-37 decreased the peak level of Ca2+ fluorescence induced by thapsigargin and HDM, and inhibited the mRNA expression of Orai1, suggesting an inhibiting effect of IL-37 on SOCE in airway epithelial cells. CONCLUSION: IL-37 plays a protective role in airway inflammation and HDM-induced airway epithelial barrier dysfunction by inhibiting SOCE.

Consistent Multi-Omic Relationships Uncover Molecular Basis of Pediatric Asthma IgE Regulation.

Serum total immunoglobulin E levels (total IgE) capture the state of the immune system in relation to allergic sensitization. High levels are associated with airway obstruction and poor clinical outcomes in pediatric asthma. Inconsistent patient response to anti-IgE therapies motivates discovery of molecular mechanisms underlying serum IgE level differences in children with asthma. To uncover these mechanisms using complementary metabolomic and transcriptomic data, abundance levels of 529 named metabolites and expression levels of 22,772 genes were measured among children with asthma in the Childhood Asthma Management Program (CAMP, N=564) and the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS, N=309) via the TOPMed initiative. Gene-metabolite associations dependent on IgE were identified within each cohort using multivariate linear models and were interpreted in a biochemical context using network topology, pathway and chemical enrichment, and representation within reactions. A total of 1,617 total IgE-dependent gene-metabolite associations from GACRS and 29,885 from CAMP met significance cutoffs. Of these, glycine and guanidinoacetic acid (GAA) were associated with the most genes in both cohorts, and the associations represented reactions central to glycine, serine, and threonine metabolism and arginine and proline metabolism. Pathway and chemical enrichment analysis further highlighted additional related pathways of interest. The results of this study suggest that GAA may modulate total IgE levels in two independent pediatric asthma cohorts with different characteristics, supporting the use of L-Arginine as a potential therapeutic for asthma exacerbation. Other potentially new targetable pathways are also uncovered.

Succinate coenzyme A ligase ß-like protein from Trichinella spiralis is a potential therapeutic molecule for allergic asthma.

BACKGROUND: For decades, studies have demonstrated the anti-inflammatory potential of proteins secreted by helminths in allergies and asthma. Previous studies have demonstrated the immunomodulatory capabilities of Succinate Coenzyme A ligase beta-like protein (SUCLA-ß) derived from Trichinella spiralis, a crucial excretory product of this parasite. OBJECTIVE: To explore the therapeutic potential of SUCLA-ß in alleviating and controlling ovalbumin (OVA)-induced allergic asthma, as well as its influence on host immune modulation. METHODS: In this research, we utilized the rTs-SUCLA-ß protein derived from T. spiralis to investigate its potential in mitigating airway inflammation in a murine model of asthma induced by OVA sensitization/stimulation, both pre- and post-challenge. The treatment's efficacy was assessed by quantifying the extent of inflammation in the lungs. RESULTS: Treatment with rTs-SUCLA-ß demonstrated efficacy in ameliorating OVA-induced airway inflammation, as evidenced by a reduction in eosinophil infiltration, levels of OVA-specific Immunoglobulin E, interferon-γ, interleukin (IL)-9, and IL-17A, along with an elevation in IL-10. The equilibrium between Th17 and Treg cells plays a pivotal role in modulating the abundance of inflammatory cells within the organism, thereby ameliorating inflammation and alleviating symptoms associated with allergic asthma. CONCLUSIONS AND CLINICAL RELEVANCE: Our data revealed that T. spiralis-derived Ts-SUCLA-ß protein may inhibit the allergic airway inflammation by regulating host immune responses.

The New Paradigm: The Role of Proteins and Triggers in the Evolution of Allergic Asthma.

Epithelial barrier damage plays a central role in the development and maintenance of allergic inflammation. Rises in the epithelial barrier permeability of airways alter tissue homeostasis and allow the penetration of allergens and other external agents. Different factors contribute to barrier impairment, such as eosinophilic infiltration and allergen protease action-eosinophilic cationic proteins' effects and allergens' proteolytic activity both contribute significantly to epithelial damage. In the airways, allergen proteases degrade the epithelial junctional proteins, allowing allergen penetration and its uptake by dendritic cells. This increase in allergen-immune system interaction induces the release of alarmins and the activation of type 2 inflammatory pathways, causing or worsening the main symptoms at the skin, bowel, and respiratory levels. We aim to highlight the molecular mechanisms underlying allergenic protease-induced epithelial barrier damage and the role of immune response in allergic asthma onset, maintenance, and progression. Moreover, we will explore potential clinical and radiological biomarkers of airway remodeling in allergic asthma patients.

Tezepelumab in a case of severe asthma exacerbation and influenza-pneumonia on VV-ECMO.

We present a case of 43-year-old male patient with broadly by Omalizumab, Mepolizumab and Benralizumab pretreated allergic asthma, who suffered a near fatal exacerbation, triggered by an influenza A infection. Due to massive bronchoconstriction with consecutive hypercapnic ventilatory failure veno-venous ECMO therapy had to be implemented. Hence, guideline directed asthma therapy a substantial bronchodilatation could not be achieved. After administration of a single dose Tezepelumab, a novel TLSP-inhibitor, and otherwise unchanged therapy we documented a significant reduction in intrinsic PEEP measured via a naso-gastric balloon catheter and a narrowing in the expiratory flow curve of the ventilator within 24 hours. The consecutive ventilatory improvement allowed the successful weaning from veno-venous ECMO therapy and invasive ventilation.

[Preventive effects of allergen immunotherapy to pneumallergens]. / Prévention des manifestations allergiques par une immunothérapie aux pneumallergènes.

Allergen immunotherapy is still the only curative treatment for respiratory allergies. It is based on repeated administration of allergenic extracts to sensitized patients. It can be administered either by subcutaneous or by sublingual route. The purpose of the treatment is to modulate the immune response to a specific allergen and to alter the course of the disease over a long-term period. Numerous studies and meta-analyses have demonstrated its efficacy in terms of symptoms and quality of life improvement as well as reduction of the allergic march. Indication of allergen immunotherapy includes moderate to severe allergic rhinitis and mild to moderate allergic asthma from GINA step 3. Early intervention in sensitized patients is nowadays promoted.

L'immunothérapie allergénique représente, encore aujourd'hui, le seul traitement curatif des allergies respiratoires. Elle consiste en l'administration répétée d'extraits allergéniques auxquels le patient est allergique. Elle peut se faire par voie sous-cutanée ou sublinguale. L'objectif est de moduler la réponse immunitaire afin de réduire les symptômes de l'allergie et de modifier le cours de la maladie allergique avec des effets perdurant sur le long terme. De nombreuses études et méta-analyses ont prouvé son efficacité en termes d'amélioration symptomatique, d'amélioration de la qualité de vie mais également de la réduction de l'évolution de la marche allergique. L'immunothérapie allergénique est indiquée dans le traitement de la rhinite allergique modérée à sévère et de l'asthme allergique dès le palier 3 du GINA («Global Initiative for Asthma¼). Une utilisation plus précoce est de plus en plus mise en avant pour bénéficier des effets préventifs de la modulation immunitaire.

Evaluating the Toxocara cati extract as a therapeutic agent for allergic airway inflammation.

BACKGROUND: The hygiene hypothesis suggests that early life exposure to helminth infections can reduce hypersensitivity in the immune system. OBJECTIVE: The present study aims to evaluate the effects of Toxocara cati (T. cati) somatic products on allergic airway inflammation. METHODS: Between 2018 and 2020, T. cati adult worms were collected from stray cats in Mashhad, Iran (31 out of 186 cats), and their somatic extract was collected. Thirty BALB/c mice were equally divided into three groups, including the OVA group (sensitized and challenged with ovalbumin), the somatic administered group (received somatic extract along with ovalbumin sensitization), and the PBS group (sensitized and challenged with phosphate buffer saline). Bronchoalveolar lavage (BAL) fluid was collected to assess the number of cells, and lung homogenates were prepared for cytokine analysis. Histopathological analysis of the lungs was performed, and inflammatory cells and mucus were detected. Cytokine levels (IL-4, IL-5, IL-10) were measured using enzyme-linked immunosorbent assay (ELISA), and ovalbumin-specific immunoglobulin E (IgE) levels were determined using a capture ELISA. RESULTS: The somatic group significantly decreased regarding the lung pathological changes, including peribronchiolitis, perivasculitis, and eosinophil influx, compared to the group treated with ovalbumin alone. These changes were accompanied by a decrease in proinflammatory cytokines IL-4 and IL-5 and an increase in the anti-inflammatory cytokine IL-10, indicating a shift toward a more balanced immune response. The number of inflammatory cells in the BAL fluid was also significantly reduced in the somatic group, indicating a decrease in inflammation. CONCLUSION: These preclinical findings suggest that in experimental models, T. cati somatic extract exhibits promising potential as a therapeutic agent for mitigating allergic airway inflammation. Its observed effects on immune response modulation and reduction of inflammatory cell infiltration warrant further investigation in clinical studies to assess its efficacy and safety in human patients.

[Efficacy and safety of dust mite subcutaneous immunotherapy in children with allergic asthma： a prospective randomized controlled study]. / å°˜èž¨çš®ä¸‹å ç–«æ²»ç–—åº”ç”¨äºŽå„¿ç«¥è¿‡æ•æ€§å“®å–˜ç–—æ•ˆä¸Žå®‰å ¨æ€§çš„å‰çž»æ€§éšæœºå¯¹ç §ç ”ç©¶.

OBJECTIVES: To investigate the efficacy and safety of subcutaneous immunotherapy (SCIT) using dust mites in children with allergic asthma. METHODS: In a prospective randomized controlled study, 98 children with dust mite-induced allergic asthma were randomly divided into a control group (n=49) and an SCIT group (n=49). The control group received inhaled corticosteroid treatment, while the SCIT group additionally received a standardized three-year SCIT regimen. The two groups were compared based on peripheral blood eosinophil percentage, visual analogue score (VAS), total medication score, Asthma Control Test/Childhood Asthma Control Test scores, fractional exhaled nitric oxide (FeNO), and lung function before treatment, and at 6 months, 1 year, 2 years, and 3 years after treatment. Adverse reactions were recorded post-injection to evaluate the safety of SCIT. RESULTS: Compared with pre-treatment levels, the SCIT group showed a significant reduction in the percentage of peripheral blood eosinophils, VAS, total medication score, and FeNO, while lung function significantly improved, and asthma control levels were better 3 years after treatment (P<0.05). Compared with the control group, the SCIT group showed more significant improvement in all evaluated indicators 3 years after treatment (P<0.05). A total of 2 744 injections were administered, resulting in 157 cases (5.72%) of local adverse reactions and 4 cases (0.15%) of systemic adverse reactions, with no severe systemic adverse events. CONCLUSIONS: SCIT is an effective and safe treatment for allergic asthma in children.

Asthma control associated with anxiety and depression in asthmatic children following post-acute COVID-19.

BACKGROUND: Poor asthma control may adversely affect mental health. Our study investigates the correlation between inadequate asthma control, exhaled nitric oxide (FENO) levels, and anxiety and depression among pediatric asthma patients with COVID-19. METHODS: This prospective case-control study enrolled 520 asthmatic children (8-15 years), including 336 patients diagnosed with COVID-19 after rapid antigen testing at home and 184 age-matched asthmatic patients without COVID-19 infection. FENO and spirometry were performed 1 month after COVID-19 infection. Scores for Child Anxiety-Related Disorders (SCARED) and depression screen derived from Patient Health Questionnaire-9 (PHQ-9) to assess their mental health status. Childhood asthma control test (C-ACT), FENO levels, and spirometry were correlated with the SCARED and PHQ-9 questionnaires. RESULTS: SCARED subscales, including generalized anxiety disorder, social anxiety disorder, school avoidance, and depression scores from PHQ-9, exhibited a significant increase in asthmatic patients diagnosed with COVID-19 (p < .05). Among asthmatic children with SARS-CoV-2 infection, the poor asthma control group exhibited the highest SCARED and PHQ-9 measurements (p < .01). Multiple linear regression analysis indicated that reduced C-ACT scores and elevated FENO levels in asthmatic children with COVID-19 were significant risk factors for both anxiety and depression scores (p < .05). Lower C-ACT scales were associated with high scores of SCARED (r = -0.471) and PHQ-9 (r = -0.329) in asthmatic children (p < .001). CONCLUSIONS: The current study emphasizes the need for healthcare professionals to closely monitor asthma control in asthmatic children to prevent heightened risks of depression and anxiety during the ongoing COVID-19 pandemic.

Identification of mitochondria-related biomarkers in childhood allergic asthma.

BACKGROUND: The mechanism of mitochondria-related genes (MRGs) in childhood allergic asthma (CAS) was unclear. The aim of this study was to find new biomarkers related to MRGs in CAS. METHODS: This research utilized two CAS-related datasets (GSE40888 and GSE40732) and extracted 40 MRGs from the MitoCarta3.0 Database. Initially, differential expression analysis was performed on CAS and control samples in the GSE40888 dataset to obtain the differentially expressed genes (DEGs). Differentially expressed MRGs (DE-MRGs) were obtained by overlapping the DEGs and MRGs. Protein protein interactions (PPI) network of DE-MRGs was created and the top 10 genes in the degree ranking of Maximal Clique Centrality (MCC) algorithm were defined as feature genes. Hub genes were obtained from the intersection genes from the Least absolute shrinkage and selection operator (LASSO) and EXtreme Gradient Boosting (XGBoost) algorithms. Additionally, the expression validation was conducted, functional enrichment analysis, immune infiltration analysis were finished, and transcription factors (TFs)-miRNA-mRNA regulatory network was constructed. RESULTS: A total of 1505 DEGs were obtained from the GSE40888, and 44 DE-MRGs were obtained. A PPI network based on these 44 DE-MRGs was created and revealed strong interactions between ADCK5 and MFN1, BNIP3 and NBR1. Four hub genes (NDUFAF7, MTIF3, MRPS26, and NDUFAF1) were obtained by taking the intersection of genes from the LASSO and XGBoost algorithms based on 10 signature genes which obtained from PPI. In addition, hub genes-based alignment diagram showed good diagnostic performance. The results of Gene Set Enrichment Analysis (GSEA) suggested that hub genes were closely related to mismatch repair. The B cells naive cells were significantly expressed between CAS and control groups, and MTIF3 was most strongly negatively correlated with B cells naive. In addition, the expression of MTIF3 and MRPS26 may have influenced the inflammatory response in CAS patients by affecting mitochondria-related functions. The quantitative real-time polymerase chain reaction (qRT‒PCR) results showed that four hub genes were all down-regulated in the CAS samples. CONCLUSION: NDUFAF7, MTIF3, MRPS26, and NDUFAF1 were identified as an MRGs-related biomarkers in CAS, which provides some reference for further research on CAS.

Heat-killed Akkermansia muciniphila ameliorates allergic airway inflammation in mice.

Allergic asthma (AA) is a common inflammatory airway disease characterized by increased airway hyper-responsiveness (AHR), inflammation, and remodeling. Akkermansia muciniphila is a strictly anaerobic bacterium residing in the gut and is a promising next-generation probiotic to improve metabolic inflammatory syndrome. A recent study suggested the beneficial effect of live A. muciniphila on allergic airway inflammation (AAI) in mice. However, whether the heat-killed form can improve AAI requires further investigation. Mice sensitized and challenged with house dust mites (HDM) develop AA hallmarks including inflammatory cell infiltration, goblet cell hyperplasia, and subepithelial collagen deposition in the lungs. These phenomena were reversed by oral administration of the heat-killed A. muciniphila strain EB-AMDK19 (AMDK19-HK) isolated from the feces of healthy Koreans. Furthermore, AMDK19-HK diminished the HDM-induced AHR to inhaled methacholine, lung mast cell accumulation, and serum HDM-specific IgE levels. It also led to the overall suppression of IL-4, IL-13, and eotaxin production in bronchoalveolar lavage fluids, and Il4, Il5, Il13, and Ccl17 gene expression in lung tissues. Moreover, AMDK19-HK suppressed Th2-associated cytokine production in the splenocytes of HDM-sensitized mice in vitro. Additionally, a combination of 16S rRNA gene sequencing and short-chain fatty acid (SCFA) analysis in cecal samples revealed that AMDK19-HK modulated the relative abundance of circulating SCFA-associated gut genera, including a positive correlation with Lachnospiraceae_ NK4A136_group and a negative correlation with Lachnoclostridium and significantly increased cecal SCFA concentrations. Finally, AMDK19-HK improved intestinal mucosal barrier function. These results suggest that the oral administration of AMDK19-HK ameliorates HDM-induced AAI in mice by suppressing Th2-mediated immune responses and could have a protective effect against AA development.

Identification of plasma protein markers of allergic disease risk: a mendelian randomization approach to proteomic analysis.

BACKGROUND: While numerous allergy-related biomarkers and targeted treatment strategies have been developed and employed, there are still signifcant limitations and challenges in the early diagnosis and targeted treatment for allegic diseases. Our study aims to identify circulating proteins causally associated with allergic disease-related traits through Mendelian randomization (MR)-based analytical framework. METHODS: Large-scale cis-MR was employed to estimate the effects of thousands of plasma proteins on five main allergic diseases. Additional analyses including MR Steiger analyzing and Bayesian colocalisation, were performed to test the robustness of the associations; These findings were further validated utilizing meta-analytical methods in the replication analysis. Both proteome- and transcriptome-wide association studies approach was applied, and then, a protein-protein interaction was conducted to examine the interplay between the identified proteins and the targets of existing medications. RESULTS: Eleven plasma proteins were identified with links to atopic asthma (AA), atopic dermatitis (AD), and allergic rhinitis (AR). Subsequently, these proteins were classified into four distinct target groups, with a focus on tier 1 and 2 targets due to their higher potential to become drug targets. MR analysis and extra validation revealed STAT6 and TNFRSF6B to be Tier 1 and IL1RL2 and IL6R to be Tier 2 proteins with the potential for AA treatment. Two Tier 1 proteins, CRAT and TNFRSF6B, and five Tier 2 proteins, ERBB3, IL6R, MMP12, ICAM1, and IL1RL2, were linked to AD, and three Tier 2 proteins, MANF, STAT6, and TNFSF8, to AR. CONCLUSION: Eleven Tier 1 and 2 protein targets that are promising drug target candidates were identified for AA, AD, and AR, which influence the development of allergic diseases and expose new diagnostic and therapeutic targets.

Hispidulin Alleviates Mast Cell-Mediated Allergic Airway Inflammation through FcεR1 and Nrf2/HO-1 Signaling Pathway.

Allergic asthma is a type 2 immune-response-mediated chronic respiratory disease. Mast cell activation influences the pathogenesis and exacerbation of allergic asthma. Therefore, the development of mast cell-targeting pharmacotherapy is important for managing allergic airway inflammation. We investigated the efficacy of hispidulin (HPD), natural flavone, in a mast-cell-mediated ovalbumin (OVA)-induced allergic airway inflammation model. HPD alleviated symptoms of allergic asthma and decreased the levels of immunoglobulin (Ig) E, type 2 inflammation, immune cell infiltration, and mast cell activation in the lung. Furthermore, in vivo analysis confirmed the efficacy of HPD through the evaluation of IgE-mediated allergic responses in a mast cell line. HPD treatment inhibited mast cell degranulation through inhibition of the FcεR1 signaling pathway and suppressed the expression of inflammatory cytokines (TNF-α, IL-4, IL-6, and IL-13) through suppression of the NF-κB signaling pathway. The antioxidant effects of HPD in activated mast cells were identified through modulation of antioxidant enzymes and the Nrf2/HO-1 signaling pathway. In conclusion, HPD may be a potential therapeutic candidate for allergic airway inflammation of asthma and acts by suppressing mast cell activation and oxidative stress.

Fiber rich food suppressed airway inflammation, GATA3 + Th2 cells, and FcεRIα+ eosinophils in asthma.

Background: Allergic Asthma is a disease presenting various endotypes and no current therapies act curative but alleviate disease symptoms. Dietary interventions are gaining increasing importance in regulating immune responses. Furthermore, short chain fatty acids (SFCA), as the main products of dietary fiber's fermentation by the gut bacteria, ameliorate the pathogenesis and disease burden of different illnesses including asthma. Nevertheless, the connection and crosstalk between the gut and lung is poorly understood. Objective: In this work, the role of high fiber diet on the development of allergic asthma at baseline and after exacerbation of disease induced by respiratory viruses was investigated. Methods: Hereby, SCFA in serum of asthmatic and non-asthmatic pre-school children before and after airway disease symptoms were analyzed. Moreover, the effect of high fiber diet in vivo in a murine model of house dust mite extract (HDM) induced allergic asthma and in the end in isolated lung and spleen cells infected ex vivo with Rhinovirus was analyzed. Results: In this study, a decrease of the SCFA 3-Hydroxybutyric acid in serum of asthmatic children after symptomatic episodes at convalescent visit as compared to asthmatic and control children at baseline visit was observed. In experimental asthma, in mice fed with high fiber diet, a reduced lung GATA3 + Th2 type mediated inflammation, mucus production and collagen deposition and expression of Fc epsilon receptor Ia (FcεRIa) in eosinophils was observed. By contrast, the CD8+ memory effector T cells were induced in the lungs of asthmatic mice fed with high fiber diet. Then, total lung cells from these asthmatic mice fed with either standard food or with fiber rich food were infected with RV ex vivo. Here, RV1b mRNA was found significantly reduced in the lung cells derived from fiber rich food fed mice as compared to those derived from standard food fed asthmatic mice. Looking for the mechanism, an increase in CD8+ T cells in RV infected spleen cells derived from fiber rich fed asthmatic mice, was observed. Conclusion: Convalescent preschool asthmatic children after a symptomatic episode have less serum ß-Hydroxybutyric acid as compared to control and asthmatic children at baseline visit. Fiber rich diet associated with anti-inflammatory effects as well as anti-allergic effects by decreasing Type 2 and IgE mediated immune responses and inducing CD8+ memory effector T cells in a murine model of allergic asthma. Finally, ex vivo infection with Rhinovirus (RV) of total lung cells from asthmatic mice fed with fiber rich food led to a decreased RV load as compared to mice fed with standard food. Moreover, spleen cells derived from asthmatic mice fed with fiber rich food induced CD8+ T cells after ex vivo infection with RV. Clinical implications: Dietary interventions with increased content in natural fibers like pectins would ameliorate asthma exacerbations. Moreover, respiratory infection in asthma downregulated SCFA in the gut contributing to asthma exacerbations.

Elderly and aged asthma have different characteristics: results of a multicenter study.

Background/aim: Characteristics of asthma in the elderly population is not well-known. The aim of the present study was to evaluate asthma in the elderly population, to compare disease characteristics between patients diagnosed <60 (aged asthma) and ≥60 (elderly asthma) years of age. Materials and methods: The study was a prospective, multicenter, cross-sectional type. A questionnaire was filled out to patients 60 years of age and over, that have been followed for asthma for at least 3 months. Asthma Control Test (ACT), eight-item Morisky Medication Adherence Scale (MMAS-8) was filled out, inhaler device technique was assessed. Results: A total of 399 patients were included from 17 tertiary care centers across the country. Mean age was 67.11 years and 331 (83%) were female. The age at asthma diagnosis was ≥60 in 146 (36.6%) patients. Patients diagnosed ≥60 years were older (p < 0.001), had higher education level (p < 0.001), more commonly had first-degree relative with asthma (p = 0.038), asthma related comorbidities (p = 0.009) and accompanying rhinitis/rhinosinusitis (p = 0.005), had better asthma control (p = 0.001), were using less controller medications (p = 0.014). Inhaler technique was correct in 37% of the patients with no difference in between the groups. Treatment compliance was better in elderly asthma patients (p < 0.001). In the multivariate logistic regression analysis, having well-controlled asthma (odds ratio = 1.61, CI = 1.04-2.51), and high medication adherence rate (odds ratio = 2.43, CI = 1.48-4.0) were associated with being in the elderly asthma group. Conclusion: The characteristics of asthma are different among patients aged 60 years and over which seems to be related to onset age of asthma. In our cohort, the elderly asthma patients had higher education level, and treatment adherence and asthma control was better. Patients diagnosed ≥60 years of age did not have more severe disease.

Iron-related Genes and Proteins Involved in Iron Homeostasis in Animal Models of Allergic Asthma: A Systematic Review.

The involvement of the immune oxidative stress response in the pathophysiology and pathogenesis of allergic asthma is well documented. However, reports on the role of iron homeostasis in allergic asthma is scarce. Therefore, this study aims to identify iron-related genes and proteins in mouse models of allergic asthma. Related articles were identified from SCOPUS and Web of Science databases. The article search was limited to publications in English, within a 10-year period (2014 - 2023, up to 16 August 2023) and original/research papers. All identified articles were screened for eligibility using the inclusion and exclusion criteria. All eligible articles were quality appraised prior to data extraction. Five studies were selected for data extraction. Based on the extracted data, three themes and seven subthemes related to iron homeostasis were identified. The type of samples and analytical methods used were also identified. In conclusion, our study elucidates that iron-related proteins are regulated in animal models of allergic asthma. However, the currently available data do not allow us to conclude whether the disease model resulted in iron accumulation or depletion. Therefore, further studies with other related markers should be conducted.