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Particle and Fibre Toxicology Aug 2023Pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) has been reported to exert strong pro-inflammatory and pro-fibrotic adjuvant effects in mouse models of...
BACKGROUND
Pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) has been reported to exert strong pro-inflammatory and pro-fibrotic adjuvant effects in mouse models of allergic lung disease. However, the molecular mechanisms through which MWCNTs exacerbate allergen-induced lung disease remain to be elucidated. We hypothesized that protease-activated receptor 2 (PAR2), a G-protein coupled receptor previously implicated in the pathogenesis of various diseases including pulmonary fibrosis and asthma, may play an important role in the exacerbation of house dust mite (HDM) allergen-induced lung disease by MWCNTs.
METHODS
Wildtype (WT) male C57BL6 mice and Par2 KO mice were exposed to vehicle, MWCNTs, HDM extract, or both via oropharyngeal aspiration 6 times over a period of 3 weeks and were sacrificed 3-days after the final exposure (day 22). Bronchoalveolar lavage fluid (BALF) was harvested to measure changes in inflammatory cells, total protein, and lactate dehydrogenase (LDH). Lung protein and RNA were assayed for pro-inflammatory or profibrotic mediators, and formalin-fixed lung sections were evaluated for histopathology.
RESULTS
In both WT and Par2 KO mice, co-exposure to MWCNTs synergistically increased lung inflammation assessed by histopathology, and increased BALF cellularity, primarily eosinophils, as well as BALF total protein and LDH in the presence of relatively low doses of HDM extract that alone produced little, if any, lung inflammation. In addition, both WT and par2 KO mice displayed a similar increase in lung Cc1-11 mRNA, which encodes the eosinophil chemokine CCL-11, after co-exposure to MWCNTs and HDM extract. However, Par2 KO mice displayed significantly less airway fibrosis as determined by quantitative morphometry compared to WT mice after co-exposure to MWCNTs and HDM extract. Accordingly, at both protein and mRNA levels, the pro-fibrotic mediator arginase 1 (ARG-1), was downregulated in Par2 KO mice exposed to MWCNTs and HDM. In contrast, phosphorylation of the pro-inflammatory transcription factor NF-κB and the pro-inflammatory cytokine CXCL-1 was increased in Par2 KO mice exposed to MWCNTs and HDM.
CONCLUSIONS
Our study indicates that PAR2 mediates airway fibrosis but not eosinophilic lung inflammation induced by co-exposure to MWCNTs and HDM allergens.
Topics: Animals; Male; Mice; Allergens; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Fibrosis; Hypersensitivity; Lung; Mice, Inbred C57BL; Nanotubes, Carbon; Pneumonia; Pulmonary Fibrosis; Pyroglyphidae; Receptor, PAR-2; RNA, Messenger
PubMed: 37580758
DOI: 10.1186/s12989-023-00538-6 -
Chinese Medical Journal Sep 2023
Topics: Animals; Humans; Thymic Stromal Lymphopoietin; Pyroglyphidae; Cytokines; Asthma; Respiratory System; Epithelial Cells
PubMed: 37469013
DOI: 10.1097/CM9.0000000000002615 -
Respiratory Research Jul 2023Accumulating clinical evidence links Obstructive Sleep Apnea (OSA) with worse outcomes of asthma, but impact on airway function remains sparsely studied. We tested...
INTRODUCTION
Accumulating clinical evidence links Obstructive Sleep Apnea (OSA) with worse outcomes of asthma, but impact on airway function remains sparsely studied. We tested effects of Chronic Intermittent Hypoxia (CIH) - a hallmark of OSA - on airway hyperresponsiveness (AHR), in a rat model of chronic allergen-induced inflammation.
METHODS
Brown Norway rats were exposed to six weeks of CIH or normoxia (NORM) concurrent with weekly house dust mites (HDM) or saline (SAL) challenges. At endpoint, we assessed responses to seven Methacholine (Mch) doses (0, 4, 8, 16, 32, 64, 128 mg/mL) on a FlexiVent system (Scireq). Maximal (or plateau) responses (reactivity) for total respiratory system Resistance (R) and Elastance (E), Newtonian airway resistance (R a measure of central airways function) and tissue damping (G, a measure of distal airways function) were plotted.
RESULTS
HDM/CIH-treated animals demonstrated the highest reactivity to Mch in R and E compared to all other groups (HDM/NORM, SAL/CIH and SAL/NORM p < 0.05 for all comparisons, for doses 5-7 for R, and for doses 4-7 for E). The enhanced R response was due to an increase in G (doses 4-7, p < 0.05 for comparisons to all other groups), whereas R was not affected by CIH.
CONCLUSIONS
In rats chronically challenged with HDM, concurrent CIH exposure induces AHR primarily in the distal airways, which affects the respiratory system frequency-dependent elastic properties.
Topics: Rats; Animals; Pyroglyphidae; Allergens; Respiratory Hypersensitivity; Lung; Hypoxia; Methacholine Chloride; Inflammation; Sleep Apnea, Obstructive; Disease Models, Animal
PubMed: 37468919
DOI: 10.1186/s12931-023-02493-4 -
ACS Nano Aug 2023It has been shown that inhalation exposure to copper oxide nanoparticles (CuO NPs) results in pulmonary inflammation. However, immunomodulatory consequences after CuO NP...
It has been shown that inhalation exposure to copper oxide nanoparticles (CuO NPs) results in pulmonary inflammation. However, immunomodulatory consequences after CuO NP inhalation exposure have been less explored. We tested the effect of CuO NP aerosols on immune responses in healthy, house dust mite (HDM) asthmatic, or allergen immunotherapy (AIT)-treated asthmatic mice (BALB/c, females). The AIT consisted of a vaccine comprising HDM allergens and CpG-loaded nanoparticles (CpG NPs). AIT treatment involved mice being immunized (via subcutaneous (sc) injection; 2 doses) while concomitantly being exposed to CuO NP aerosols (over a 2 week period), starting on the day of the first vaccination. Mice were then sensitized twice by sc injection and subsequently challenged with HDM extract 10 times by intranasal instillation. The asthmatic model followed the same timeline except that no immunizations were administered. All mice were necropsied 24 h after the end of the HDM challenge. CuO NP-exposed healthy mice showed a significant decrease in T1 and T2 cells, and an elevation in T-bet Treg cells, even 40 days after the last exposure to CuO NPs. Similarly, the CuO NP-exposed HDM asthma model demonstrated decreased T2 responses and increased T-bet Treg cells. Conversely, CuO NP inhalation exposure to AIT-treated asthmatic mice resulted in an increase in T2 cells. In conclusion, immunomodulatory effects of inhalation exposure to CuO NPs are dependent on immune conditions prior to exposure.
Topics: Female; Mice; Animals; Copper; Inhalation Exposure; Asthma; Pyroglyphidae; Immunity; Nanoparticles; Oxides
PubMed: 37463491
DOI: 10.1021/acsnano.3c01668 -
Cell Death & Disease Jul 2023Polymerase 1 and transcript release factor (PTRF, encoding by Cavin-1) regulates interleukin 33 (IL-33) release, which is implicated in asthma development. Z-DNA binding...
Polymerase 1 and transcript release factor (PTRF, encoding by Cavin-1) regulates interleukin 33 (IL-33) release, which is implicated in asthma development. Z-DNA binding protein 1 (ZBP1)-sensing Z-RNAs induces necroptosis which causes inflammatory diseases. House dust mite (HDM) is the major source of allergen in house dust and is strongly associated with the development of asthma. Whether PTRF via IL-33 and ZBP1 mediates HDM-induced macrophage necroptosis and airway inflammation remains unclear. Here, we found that deficiency of PTRF could reduce lung IL-33, ZBP1, phosphor-receptor-interacting protein kinase 3 (p-RIPK3), and phosphor-mixed lineage kinase domain-like (p-MLKL) (necroptosis executioner), and airway inflammation in an HDM-induced asthma mouse model. In HDM-treated macrophages, ZBP1, p-RIPK3, and p-MLKL levels were markedly increased, and these changes were reversed by deletion of Cavin-1. Deletion of Il33 also reduced expression of ZBP1, p-RIPK3, and p-MLKL in HDM-challenged lungs. Moreover, IL-33 synergizing with HDM boosted expression of ZBP1, p-RIPK3, and p-MLKL in macrophages. In bronchial epithelial cells rather than macrophages and vascular endothelial cells, PTRF positively regulates IL-33 expression. Therefore, we conclude that PTRF mediates HDM-induced macrophage ZBP1/necroptosis and airway inflammation, and this effect could be boosted by bronchial epithelial cell-derived IL-33. Our findings suggest that PTRF-IL33-ZBP1 signaling pathway might be a promising target for dampening airway inflammation.
Topics: Animals; Mice; Interleukin-33; Pyroglyphidae; Necroptosis; Endothelial Cells; Asthma; Macrophages; Protein Kinases; Signal Transduction; Inflammation
PubMed: 37454215
DOI: 10.1038/s41419-023-05971-1 -
Microbiology Spectrum Aug 2023House dust mites (HDMs) are a major source of indoor allergens that cause airway allergic disease. , a predominant species of HDMs in China, has demonstrated pathogenic...
House dust mites (HDMs) are a major source of indoor allergens that cause airway allergic disease. , a predominant species of HDMs in China, has demonstrated pathogenic role in allergic disorders. Exosomes derived from human bronchoalveolar lavage fluid have been strongly associated with allergic respiratory diseases progression. However, the pathogenic role of -derived exosomes in allergic airway inflammation has remained unclear until now. Here, was stirred overnight in phosphate-buffered saline, and the supernatant was used to extract exosomes by ultracentrifugation. Then, shotgun liquid chromatography-tandem mass spectrometry and small RNA sequencing were performed to identify proteins and microRNAs contained in exosomes. Immunoblotting, Western blotting, and enzyme-linked immunosorbent assay demonstrated the specific immunoreactivity of -specific serum IgE antibody against exosomes, and exosomes were found to induce allergic airway inflammation in a mouse model. In addition, exosomes invaded 16-HBE bronchial epithelial cells and NR8383 alveolar macrophages to release the inflammation-related cytokines interleukin-33 (IL-33), thymic stromal lymphopoietin, tumor necrosis factor alpha, and IL-6, and comparative transcriptomic analysis of 16-HBE and NR8383 cells revealed that immune pathways and immune cytokines/chemokines were involved in the sensitization of exosomes. Taken together, our data demonstrate that exosomes are immunogenic and may induce allergic airway inflammation via bronchial epithelial cells and alveolar macrophages. , a predominant species of house dust mites in China, has displayed pathogenic role in allergic disorders, and exosomes derived from human bronchoalveolar lavage fluid have been strongly associated with allergic respiratory diseases progression. However, the pathogenic role of -derived exosomes in allergic airway inflammation has remained unclear until now. This study, for the first time, extracted exosomes from , and sequenced their protein cargo and microRNAs using shotgun liquid chromatography-tandem mass spectrometry and small RNA sequencing. -derived exosomes trigger allergen-specific immune responses and present satisfactory immunogenicity, as revealed by immunoblotting, Western blotting, and enzyme-linked immunosorbent assay and may induce allergic airway inflammation via bronchial epithelial cells and alveolar macrophages. Our data provide insights into the mechanisms of allergic airway inflammation caused with -derived exosomes and the treatment of house dust mite-induced allergic airway inflammation.
Topics: Animals; Mice; Humans; Dermatophagoides farinae; Exosomes; Inflammation; Allergens; Cytokines; MicroRNAs; Respiratory Tract Diseases
PubMed: 37314339
DOI: 10.1128/spectrum.05054-22 -
Environmental Pollution (Barking, Essex... Jul 2023Experimental studies suggest that neutrophils could contribute to allergic asthma pathogenesis, that is mainly driven by type 2 immunity. Inhalation of diesel exhaust...
Experimental studies suggest that neutrophils could contribute to allergic asthma pathogenesis, that is mainly driven by type 2 immunity. Inhalation of diesel exhaust particles (DEP) is implicated in both exacerbation and development of asthma. Since exposure to DEP is associated with a neutrophilic component, we aimed to investigate how exposure to the combination of allergens and DEP modulates neutrophilic responses. Human bronchial epithelial cells (HBEC) were exposed to house dust mite (HDM), DEP or HDM + DEP in vitro to determine the expression of neutrophil-recruiting chemokines. Female (C57BL/6 J) mice were intranasally instilled with saline, DEP, HDM or combined HDM + DEP for 3 weeks (subacute) or 6 weeks (chronic). The neutrophilic responses were determined in lung tissue and bronchoalveolar lavage fluid (BALF). Simultaneous exposure to HDM + DEP resulted in increased CXCL1 and CXCL8 mRNA expression by HBEC in vitro. In mice, subacute exposure to HDM + DEP induced a strong mixed eosinophilic/neutrophilic inflammation in BALF and lung and was associated with higher expression of neutrophil-attracting chemokines and NET formation compared to the sole exposures. After chronic HDM + DEP exposure, a similar neutrophilic response was observed, however the NET formation was less pronounced. Interestingly, the increase of BALF eosinophils was also significantly attenuated after chronic HDM + DEP exposure compared to the subacute exposure. Subacute and chronic HDM + DEP exposure induced goblet cell hyperplasia and airway hyperresponsiveness. Our data suggest a role for neutrophils and NETs in pollutant-aggravated eosinophilic allergic asthma. Moreover, subacute exposure to HDM + DEP induces a mixed eosinophilic/neutrophilic response whereas upon chronic HDM + DEP exposure there is a shift in inflammatory response with a more prominent neutrophilic component.
Topics: Female; Humans; Mice; Animals; Environmental Pollutants; Mice, Inbred C57BL; Asthma; Lung; Hypersensitivity; Disease Models, Animal; Allergens; Pyroglyphidae
PubMed: 37105460
DOI: 10.1016/j.envpol.2023.121722 -
Tissue Barriers Jan 2024House dust mite (HDM) is a common aeroallergen that can disrupt the airway epithelial barrier leading to dysregulated immune response, resulting in allergic lung...
House dust mite (HDM) is a common aeroallergen that can disrupt the airway epithelial barrier leading to dysregulated immune response, resulting in allergic lung diseases such as asthma. Cryptochrome (CRY), a circadian clock gene, plays an important role in the regulation of metabolism, and immune response. It remains unclear whether stabilizing CRY using KL001 can attenuate HDM/Th2 cytokine-induced epithelial barrier dysfunction in 16-HBE cells. We evaluate the effect of KL001 (20 µM) pre-treatment (4 hrs) in HDM/Th2 cytokine (IL-4 or IL-13)-mediated change in epithelial barrier function. HDM and Th2 cytokine-induced changes in transepithelial electrical resistance (TEER) were determined by an xCELLigence real-time cell analyzer and delocalization of adherens junction complex (AJC: E-cadherin and β-catenin) and tight junction proteins (TJP: Occludin and Zonula occludens-1) by immunostaining and confocal microscopy. Finally, quantitative real-time PCR (qRT-PCR) and Western blotting were used to measure altered gene expression and protein abundance of the epithelial barrier function and core clock genes, respectively. HDM and Th2 cytokine treatment significantly decreased TEER associated with altered gene expression and protein abundance of the selected epithelial barrier function and circadian clock genes. However, pre-treatment with KL001 attenuated HDM and Th2 cytokine-induced epithelial barrier dysfunction as early as 12-24 hrs. KL001 pre-treatment showed attenuation of HDM and Th2 cytokine-induced alteration in the localization and gene expression of AJP and TJP ( and ) and core clock genes ( and ). We demonstrate, for the first time, the protective role of KL001 in HDM and Th2 cytokine-mediated epithelial barrier dysfunction.
Topics: Animals; Pyroglyphidae; Cytokines; Cell Line; Hypersensitivity; Carbazoles; Sulfonamides
PubMed: 37079442
DOI: 10.1080/21688370.2023.2203841 -
Allergology International : Official... Oct 2023We aimed to compare the effectiveness and safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) with standardized house dust mite (HDM) extract...
BACKGROUND
We aimed to compare the effectiveness and safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) with standardized house dust mite (HDM) extract for allergic rhinitis.
METHODS
Participants with allergic rhinitis selected their treatment between HDM SCIT or HDM SLIT, according to their wishes. We prospectively followed symptoms of allergic rhinitis using the allergic rhinitis symptom medication score (ARSMS), along with adverse reactions, during the dose escalation and maintenance phases for two years. We compared the outcomes between propensity score-matched groups to adjust the confounding factors.
RESULTS
After propensity score matching, 88 patients in the HDM SCIT (n = 44) and HDM SLIT groups (n = 44) remained for analysis. The HDM SCIT group showed significantly earlier effectiveness than the HDM SLIT group (median time to decrease in ARSMS [≥2 points]: 5.5 vs. 18.0 months, p < 0.001). The incidence of systemic reactions was not significantly different between the two groups in the dose escalation phase (68.2% vs. 56.8%, p = 0.379). In the maintenance phase, the incidence of systemic reactions was higher in the HDM SCIT group than in the HDM SLIT group (18.2% vs. 0%, p < 0.006). All 44 patients in the HDM SCIT group completed two years of treatment, while nine patients in the HDM SLIT group discontinued treatment.
CONCLUSIONS
The HDM SCIT group showed an earlier onset of therapeutic effect and a lower discontinuation rate than the HDM SLIT group, although more severe systemic reactions were observed during the maintenance phase.
Topics: Animals; Humans; Child; Sublingual Immunotherapy; Desensitization, Immunologic; Prospective Studies; Pyroglyphidae; Injections, Subcutaneous; Rhinitis, Allergic; Allergens; Treatment Outcome; Antigens, Dermatophagoides
PubMed: 36918306
DOI: 10.1016/j.alit.2023.02.007 -
European Annals of Allergy and Clinical... Mar 2024The sensitization profile of patients allergic to house dust mites (HDM) and its molecular diagnosis may determine treatment and evolution of the disease. The present...
The sensitization profile of patients allergic to house dust mites (HDM) and its molecular diagnosis may determine treatment and evolution of the disease. The present study investigates the prevalence of Der p 23 sensitization and its relation to asthma in a population of HDM-allergic patients. We conducted a cross-sectional study of 891 patients with HDM allergy with symptoms of rhinitis and 52.1% of them with asthma. Total and specific IgE (sIgE) was measured against and its molecular components and the storage mite using ImmunoCAP. Prevalence of sensitization and levels of sIgE were analyzed according to asthma diagnosis and asthma severity. Der p 23 was the predominant allergen in this population (83.7%), but IgE levels were lower than those of sIgE to Der p 1 and Der p 2. A good correlation was found between sIgE to Der p 23 and the other allergens. A total of 8.2% patients were monosensitized to Der p 23. Asthma was more frequent in patients with positive sIgE against Der p 23 than in patients without this sensitization (p = 0.027). A tendency to increase both total IgE and sIgE was observed in relation to the severity of asthma from intermittent mild asthma to persistent moderate asthma, but a substantial decrease in total IgE and sIgE was detected in more severe asthmatics. Der p 23 might be a prevalent allergen in regions with high rates of HDM exposure and its presence could increase the risk of asthma.
Topics: Animals; Humans; Cross-Sectional Studies; Antigens, Dermatophagoides; Immunoglobulin E; Pyroglyphidae; Asthma; Hypersensitivity; Allergens
PubMed: 35899400
DOI: 10.23822/EurAnnACI.1764-1489.264