-
American Journal of Physiology. Lung... Dec 2023Asthma susceptibility is influenced by environmental, genetic, and epigenetic factors. DNA methylation is one form of epigenetic modification that regulates gene...
Asthma susceptibility is influenced by environmental, genetic, and epigenetic factors. DNA methylation is one form of epigenetic modification that regulates gene expression and is both inherited and modified by environmental exposures throughout life. Prenatal development is a particularly vulnerable time period during which exposure to maternal asthma increases asthma risk in offspring. How maternal asthma affects DNA methylation in offspring and what the consequences of differential methylation are in subsequent generations are not fully known. In this study, we tested the effects of grandmaternal house dust mite (HDM) allergen sensitization during pregnancy on airway physiology and inflammation in HDM-sensitized and challenged second-generation mice. We also tested the effects of grandmaternal HDM sensitization on tissue-specific DNA methylation in allergen-naïve and -sensitized second-generation mice. Descendants of both allergen- and vehicle-exposed grandmaternal founders exhibited airway hyperreactivity after HDM sensitization. However, grandmaternal allergen sensitization significantly potentiated airway hyperreactivity and altered the epigenomic trajectory in second-generation offspring after HDM sensitization compared with HDM-sensitized offspring from vehicle-exposed founders. As a result, biological processes and signaling pathways associated with epigenetic modifications were distinct between lineages. A targeted analysis of pathway-associated gene expression found that Smad3 was significantly dysregulated as a result of grandmaternal allergen sensitization. These data show that grandmaternal allergen exposure during pregnancy establishes a unique epigenetic trajectory that reprograms allergen responses in second-generation offspring and may contribute to asthma risk. Asthma susceptibility is influenced by environmental, genetic, and epigenetic factors. This study shows that maternal allergen exposure during pregnancy promotes unique epigenetic trajectories in second-generation offspring at baseline and in response to allergen sensitization, which is associated with the potentiation of airway hyperreactivity. These effects are one mechanism by which maternal asthma may influence the inheritance of asthma risk.
Topics: Pregnancy; Humans; Female; Mice; Animals; Allergens; Epigenomics; Prenatal Exposure Delayed Effects; Asthma; Disease Susceptibility; Epigenesis, Genetic; Pyroglyphidae
PubMed: 37814791
DOI: 10.1152/ajplung.00103.2023 -
Scientific Reports Oct 2023A subgroup of patients suffering from atopic dermatitis (AD) does not respond to biologics therapy targeting the key players of type-2 inflammation, and it is an ongoing...
A subgroup of patients suffering from atopic dermatitis (AD) does not respond to biologics therapy targeting the key players of type-2 inflammation, and it is an ongoing discussion whether skin-infiltrating Th17 cells may underlie this phenomenon. This study aimed to investigate the potential of allergen-induced, immune-cell derived IL-17 on the induction of inflammatory processes in keratinocytes. Peripheral blood mononuclear cells derived from respectively sensitized AD patients were stimulated with house dust mite (HDM) extract and cell culture supernatants were applied subsequently in absence or presence of secukinumab to primary human keratinocytes. Hereby we confirm that the immune response of sensitized AD patients to HDM contains aside from type-2 cytokines significant amounts of IL-17. Blocking IL-17 efficiently reduced the stimulation-induced changes in keratinocyte gene expression. IL-17-dependent transcriptional changes included increased expression of the cytokines IL-20 and IL-24 as well as Suppressor of Cytokine Siganling 3 (SOCS3), a negative feedback-regulator of the STAT3/IL-17/IL-24 immune response. We conclude that the immune response to HDM can induce pro-inflammatory cytokines from keratinocytes in AD, which in part is mediated via IL-17. Targeting IL-17 may turn out to be a reasonable alternative therapy in a subgroup of patients with moderate to severe AD and HDM sensitization.
Topics: Animals; Humans; Allergens; Cytokines; Dermatitis, Atopic; Dermatophagoides pteronyssinus; Interleukin-17; Keratinocytes; Leukocytes, Mononuclear; Pyroglyphidae
PubMed: 37789035
DOI: 10.1038/s41598-023-42595-z -
Immunity, Inflammation and Disease Oct 2023Maintenance doses for allergen immunotherapy (AIT) have been recommended for at least 3 years but little data on long-term efficacy is available depending on AIT...
BACKGROUND
Maintenance doses for allergen immunotherapy (AIT) have been recommended for at least 3 years but little data on long-term efficacy is available depending on AIT duration. To show sustained efficacy 10 years after completion of treatment with depigmented-polymerized house dust mite (dpg-pol HDM) allergen extract in adults with asthma and/or rhinoconjunctivitis.
METHODS
Patients included in a double-blind placebo-controlled AIT study with dpg-pol HDM allergen extract were reviewed at completion of the perennial treatment and 10-year follow-up (10y-FU). Change in symptom and rescue medication score was the primary objective. Visual analog scale (VAS), asthma control test (ACT), and degree of disease control were the secondary objectives. A comparative analysis between patients who underwent AIT treatment for <3 years and ≥3 years was performed.
RESULTS
Data from 31 patients (mean age 38 years) were available at 10y-FU. All had asthma and 29 had rhinoconjunctivitis at baseline. Twenty-three patients were treated ≥3 years and 8 for <3 years. Seventeen (55%) patients were asymptomatic at completion of AIT, with significant differences for nasal, conjunctival, and bronchial symptoms (p < .0001) compared with baseline only in those patients treated ≥3 years. Nine (52.9%) patients remained completely asymptomatic at 10y-FU, all were treated for ≥3 years. Moreover, significant reduction in the number of patients with rhinitis (p = .0117), conjunctivitis (p < .0001), and bronchial (p = .0005) symptoms was observed at 10y-FU compared with baseline only in the ≥3 years treated. Ten (32.3%) patients did not require any rescue medication at 10y-FU, all had been treated for ≥3 years. ACT at 10y-FU showed a good control of asthma (median 23.5; 95% IC[22.0, 25.0]). No significant differences were observed between VAS at end of treatment compared with VAS at 10y-FU.
CONCLUSIONS
Sustained clinical efficacy is achieved 10 years after completion of depigmented-polymerized HDM, however, these findings were observed only if patients are treated for at least 3 years.
Topics: Adult; Animals; Humans; Allergens; Asthma; Dermatophagoides pteronyssinus; Desensitization, Immunologic; Follow-Up Studies; Pyroglyphidae; Rhinitis, Allergic; Double-Blind Method
PubMed: 37904678
DOI: 10.1002/iid3.1004 -
British Journal of Pharmacology Jul 2024Asthma is characterized by airway inflammation, mucus hypersecretion, and airway hyperresponsiveness. The use of nicotinic agents to mimic the cholinergic...
BACKGROUND AND PURPOSE
Asthma is characterized by airway inflammation, mucus hypersecretion, and airway hyperresponsiveness. The use of nicotinic agents to mimic the cholinergic anti-inflammatory pathway (CAP) controls experimental asthma. Yet, the effects of vagus nerve stimulation (VNS)-induced CAP on allergic inflammation remain unknown.
EXPERIMENTAL APPROACH
BALB/c mice were sensitized and challenged with house dust mite (HDM) extract and treated with active VNS (5 Hz, 0.5 ms, 0.05-1 mA). Bronchoalveolar lavage (BAL) fluid was assessed for total and differential cell counts and cytokine levels. Lungs were examined by histopathology and electron microscopy.
KEY RESULTS
In the HDM mouse asthma model, VNS at intensities equal to or above 0.1 mA (VNS 0.1) but not sham VNS reduced BAL fluid differential cell counts and alveolar macrophages expressing α7 nicotinic receptors (α7nAChR), goblet cell hyperplasia, and collagen deposition. Besides, VNS 0.1 also abated HDM-induced elevation of type 2 cytokines IL-4 and IL-5 and was found to block the phosphorylation of transcription factor STAT6 and expression level of IRF4 in total lung lysates. Finally, VNS 0.1 abrogated methacholine-induced hyperresponsiveness in asthma mice. Prior administration of α-bungarotoxin, a specific inhibitor of α7nAChR, but not propranolol, a specific inhibitor of β2-adrenoceptors, abolished the therapeutic effects of VNS 0.1.
CONCLUSION AND IMPLICATIONS
Our data revealed the protective effects of VNS on various clinical features in allergic airway inflammation model. VNS, a clinically approved therapy for depression and epilepsy, appears to be a promising new strategy for controlling allergic asthma.
Topics: Animals; alpha7 Nicotinic Acetylcholine Receptor; Vagus Nerve Stimulation; Mice, Inbred BALB C; Asthma; Mice; Bronchoalveolar Lavage Fluid; Lung; Pyroglyphidae; Inflammation; Cytokines; Female; Disease Models, Animal
PubMed: 38430056
DOI: 10.1111/bph.16334 -
Biomedicine & Pharmacotherapy =... Oct 2023Asthma is a chronic inflammatory disease that has been associated with insufficient vegetable intake. Allyl Isothiocyanate (AITC) is a natural isothiocyanate found in...
Allyl isothiocyanate mitigates airway inflammation and constriction in a house dust mite-induced allergic asthma model via upregulation of tight junction proteins and the TRPA1 modulation.
Asthma is a chronic inflammatory disease that has been associated with insufficient vegetable intake. Allyl Isothiocyanate (AITC) is a natural isothiocyanate found in cruciferous plants with anti-inflammatory and antioxidant abilities. Our study aimed to investigate the potential effect of AITC on tracheal constriction in a house dust mite (HDM)-induced asthma animal model, and explore the underlying mechanisms. To investigate the effects of AITC on HDM-induced allergic asthma model, established by intranasally administering extracts of HDM and AITC or DEX was given orally for four weeks. Flexivent SCIREQ, H&E staining, ELISA were employed to evaluate the lung function and the cytokine secretion. Possible mechanisms were determined by Western blot. Rat tracheae contraction was measured by Labscribe. We utilized lung epithelial cells (BEAS-2B) to assess the adhesion response to the combination of inflammatory factors TNF-α and IL-4. The results of the study showed that AITC significantly reduced tracheal constriction in ex vivo experiments and improved lung function in in vivo experiments compared to HDM-induced mice. Additionally, AITC decreased cytokine secretion, inflammatory cell infiltration in the lung, and constriction-related proteins expression in both lung and tracheae. Moreover, AITC increased tight junction-related protein expression in lung tissues. In vitro experiments showed that AITC had a protective effect through TRPA1 channel without affecting cell viability. Our results demonstrate that AITC has potential anti-asthma effects in HDM-induced asthma models by alleviating airway inflammation and airway constriction through increasing tight junction-related protein expression and suppressing Ca signaling. These findings suggest that AITC may be a beneficial adjuvant therapy in asthma treatment.
Topics: Rats; Animals; Mice; Pyroglyphidae; Up-Regulation; Constriction; Isothiocyanates; Asthma; Constriction, Pathologic; Inflammation
PubMed: 37634475
DOI: 10.1016/j.biopha.2023.115334 -
Turkiye Parazitolojii Dergisi Sep 2023This study was carried out to detect house dust mites in houses and to investigate group 1 antigens of Dermatophagoid species in Ordu, Giresun, Trabzon and Rize...
OBJECTIVE
This study was carried out to detect house dust mites in houses and to investigate group 1 antigens of Dermatophagoid species in Ordu, Giresun, Trabzon and Rize provinces of the Central and Eastern Black Sea Region.
METHODS
Dust samples obtained from the beds were subjected to both microscopic and antigenic examination. Samples prepared by the lactic acid method for microscopic examination were evaluated under a light microscope. Antigenic analysis was performed by investigating Der p 1 and Der f 1 belonging to and by ELISA test.
RESULTS
90.3% of the dust samples were evaluated positive by microscopic examination (10x, 40x) and 149 mites were detected. 74%, 13%, spp. growth forms 5%, spp. 1%, 1%, 1%, 1%, 1% and unidentified mites were detected at the rate of 3% respectively. Der p 1 antigen was detected in 93% and Der f 1 antigen in 84.7%. The highest amount of antigen detected in one gram of powder was 1,272 μg for Der p 1 and 0,482 μg for Der f 1.
CONCLUSION
No difference was observed between mite species and distribution in the provinces where the study was conducted (p<0.05). Dermatophagoides were found in 93% of the population. The low (4%) rate of storage/food mites is related to the fact that samples were not taken from the floors. Antigen accumulation may be important in the beds since the activity of the mites is observed throughout the year in temperate and humid regions. It is thought that this diagnosis method can be used and can be taken into account in terms of the environments in which sensitive people live.
Topics: Humans; Animals; Pyroglyphidae; Prevalence; Dermatophagoides pteronyssinus; Dust
PubMed: 37724368
DOI: 10.4274/tpd.galenos.2023.35744 -
Thorax Mar 2024Hypersensitivity to house dust mite (HDM) allergens is a common cause of allergic asthma symptoms and can be effectively treated with allergy immunotherapy (AIT). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Hypersensitivity to house dust mite (HDM) allergens is a common cause of allergic asthma symptoms and can be effectively treated with allergy immunotherapy (AIT).
OBJECTIVE
To investigate whether genetic and type 2 (T2) inflammatory biomarkers correlate with disease severity in subjects with allergic asthma, and whether this can be modified by AIT.
METHODS
MITRA (NCT01433523) was a phase III, randomised, double-blind, placebo-controlled trial of HDM sublingual immunotherapy (SLIT)-tablets in adults with HDM allergic asthma. Post hoc analyses of the study population (N=742) evaluated associations between T2 inflammatory (blood eosinophils, eosinophil cationic protein (ECP), total IgE and tryptase) and genetic (single-nucleotide polymorphisms, SNP) biomarkers (n=582) for the primary study endpoint (time to first moderate/severe asthma exacerbation). SNP associations were verified in HDM-positive subgroup from an independent 3-year Severe Asthma Research Programme (SARP3) subject cohort.
RESULTS
An increased asthma exacerbation risk in subjects homozygous for SNP rs7216389 (chromosomal locus 17q12-21) was reduced (p0.037) by treatment with HDM SLIT (HR=0.37 (95% CI 0.22 to 0.64), p<0.001). The associations between exacerbation risk and 17q12-21 SNPs were replicated in the SARP3 HDM-positive subgroup. High levels of T2 biomarkers were associated with increased risk of asthma exacerbations in the placebo group. HDM SLIT-tablet treatment reduced this risk (blood eosinophils: HR=0.50 (95% CI 0.30 to 0.85); ECP: HR=0.45 (95% CI 0.29 to 0.87); tryptase: HR=0.45 (95% CI 0.25 to 0.80)). The treatment effect was higher (p0.006) for subjects with a higher number of elevated T2 biomarkers.
CONCLUSIONS
HDM SLIT-tablet AIT is efficacious in HDM-sensitised asthma subjects with a genetic asthma predisposition and/or an underlying T2 endotype.
TRIAL REGISTRATION NUMBER
NCT01433523.
Topics: Adult; Animals; Humans; Sublingual Immunotherapy; Tryptases; Pyroglyphidae; Treatment Outcome; Hypersensitivity; Asthma; Antigens, Dermatophagoides; Tablets; Biomarkers; Allergens
PubMed: 38160049
DOI: 10.1136/thorax-2023-220707 -
International Journal of Molecular... Mar 2024Environmental pollutants are closely linked to lung cancer. The different types of environmental pollutants can be classified as chemical, physical, and biological. The... (Review)
Review
Environmental pollutants are closely linked to lung cancer. The different types of environmental pollutants can be classified as chemical, physical, and biological. The roles of common chemical and physical pollutants such as PM2.5, smoking, radon, asbestos, and formaldehyde in lung cancer have been extensively studied. Notably, the worldwide COVID-19 pandemic raised awareness of the strong link between biological pollution and human health. Allergens such as house dust mites and pollen, as well as bacteria and viruses, are common biological pollutants. A few biological pollutants have been reported to promote lung cancer via inducing inflammatory cytokines secretion, such as IL-1β, IL-6, and TGF-β, as well as suppressing immunosurveillance by upregulating regulatory T (Treg) cells while dampening the function of CD8 T cells and dendritic cells. However, the correlation between common biological hazards, such as SARS-CoV-2, human immunodeficiency viruses, , and house dust mites, and lung cancer is not fully elucidated, and the underlying mechanisms are still unclear. Moreover, the majority of studies that have been performed in lung cancer and biological carcinogens were not based on the perspective of biological pollutants, which has challenged the systematicity and coherence in the field of biological pollutants in lung cancer. Here, in addition to reviewing the recent progress made in investigating the roles of allergens, viruses, and bacteria in lung cancer, we summarized the potential mechanisms underlying biological pollutants in lung cancer. Our narrative review can shed light on understanding the significance of biological pollutants in lung cancer, as well as inspire and broaden research ideas on lung cancer etiology.
Topics: Animals; Humans; Lung Neoplasms; Environmental Pollutants; CD8-Positive T-Lymphocytes; Pandemics; Allergens; Pyroglyphidae
PubMed: 38542056
DOI: 10.3390/ijms25063081 -
Pharmaceutical Biology Dec 2024Asthma presents a global health challenge. The main pharmacotherapy is synthetic chemicals and biological-based drugs that are costly, and have significant side effects....
CONTEXT
Asthma presents a global health challenge. The main pharmacotherapy is synthetic chemicals and biological-based drugs that are costly, and have significant side effects. In contrast, use of natural products, such as onion ( L., Amaryllidaceae) in the treatment of airway diseases has increased world-wide because of their perceived efficacy and little safety concerns. However, their pharmacological actions remain largely uncharacterized.
OBJECTIVE
We investigated whether onion bulb extract (OBE) can (1) reverse established asthma phenotype (therapeutic treatment) and/or (2) prevent the development of the asthma phenotype, if given before the immunization process (preventative treatment).
MATERIALS AND METHODS
Six groups of male Balb/c mice were established for the therapeutic (21 days) and five groups for the preventative (19 days) treatment protocols; including PBS and house dust mite (HDM)-challenged mice treated with vehicle or OBE (30, 60, and 100 mg/kg/i.p.). Airways inflammation was determined using cytology, histology, immunofluorescence, Western blot, and serum IgE.
RESULTS
Therapeutic (60 mg/kg/i.p.) and preventative (100 mg/kg/i.p.) OBE treatment resulted in down-regulation of HDM-induced airway cellular influx, histopathological changes and the increase in expression of pro-inflammatory signaling pathway EGFR, ERK1/2, AKT, pro-inflammatory cytokines and serum IgE.
DISCUSSION AND CONCLUSION
Our data show that OBE is an effective anti-inflammatory agent with both therapeutic and preventative anti-asthma effects. These findings imply that onion/OBE may be used as an adjunct therapeutic agent in established asthma and/or to prevent development of allergic asthma. However, further studies to identify the active constituents, and demonstrate proof-of-concept in humans are needed.
Topics: Humans; Male; Animals; Mice; Onions; Disease Models, Animal; Asthma; Inflammation; Cytokines; Pyroglyphidae; Immunoglobulin E; Mice, Inbred BALB C; Lung
PubMed: 38584568
DOI: 10.1080/13880209.2024.2335187 -
International Immunopharmacology Feb 2024Asthma is a chronic inflammatory respiratory disease. Early-life antibiotic exposure is a unique risk factor for the incidence and severity of asthma later in life....
Asthma is a chronic inflammatory respiratory disease. Early-life antibiotic exposure is a unique risk factor for the incidence and severity of asthma later in life. Perturbations in microbial-metabolite-immune interaction caused by antibiotics are closely associated with the pathogenesis of allergy and asthma. We investigated the effect of early intervention with common oral antibiotics on later asthma exacerbations and found that different antibiotic exposures can amplify different types of immune responses induced by HDM. Cefixime (CFX) promoted a biased type 2 inflammation, azithromycin (AZM) enhanced Th17 immune response, and cefuroxime axetil (CFA) induced eosinophils recruitment. Moreover, early-life antibiotic exposure can have short- and long-term effects on the abundance, composition, and diversity of the gut microbiota. In the model of CFX-promoted type 2 airway inflammation, fecal metabolomics indicated abnormal lipid metabolism and T cell response. Lipidomic also suggested allergic airway inflammation amplified by CFX is closely associated with abnormal lipid metabolism in lung tissues. Moreover, abnormalities in lipid metabolism-related genes (LMRGs) were found to have cellular heterogeneity be associated with asthma severity by bioinformatics analysis.
Topics: Animals; Humans; Pyroglyphidae; Gastrointestinal Microbiome; Anti-Bacterial Agents; Lipid Metabolism; Lung; Asthma; Dermatophagoides pteronyssinus; Inflammation; Disease Models, Animal
PubMed: 38199196
DOI: 10.1016/j.intimp.2023.111449