Use of spirometry-like measurements to monitor house dust mite-induced experimental asthma in mice.
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ABSTRACT:
SUBMITTER: Alvarado-Vazquez PA
PROVIDER: S-EPMC8359446 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The mammalian target of rapamycin (mTOR) modulates immune responses and cellular proliferation. The objective of this study was to assess whether inhibition of mTOR with rapamycin modifies disease severity in two experimental murine models of house dust mite (HDM)-induced asthma. In an induction model, rapamycin was administered to BALB/c mice coincident with nasal HDM challenges for 3 weeks. In a treatment model, nasal HDM challenges were performed for 6 weeks and rapamycin treatment was administered during weeks 4 through 6. In the induction model, rapamycin significantly attenuated airway inflammation, airway hyperreactivity (AHR) and goblet cell hyperplasia. In contrast, treatment of established HDM-induced asthma with rapamycin exacerbated AHR and airway inflammation, whereas goblet cell hyperplasia was not modified. Phosphorylation of the S6 ribosomal protein, which is downstream of mTORC1, was increased after 3 weeks, but not 6 weeks of HDM-challenge. Rapamycin reduced S6 phosphorylation in HDM-challenged mice in both the induction and treatment models. Thus, the paradoxical effects of rapamycin on asthma severity paralleled the activation of mTOR signaling. Lastly, mediastinal lymph node re-stimulation experiments showed that treatment of rapamycin-naive T cells with ex vivo rapamycin decreased antigen-specific Th2 cytokine production, whereas prior exposure to in vivo rapamycin rendered T cells refractory to the suppressive effects of ex vivo rapamycin. We conclude that rapamycin had paradoxical effects on the pathogenesis of experimental HDM-induced asthma. Thus, consistent with the context-dependent effects of rapamycin on inflammation, the timing of mTOR inhibition may be an important determinant of efficacy and toxicity in HDM-induced asthma.
| S-EPMC3368343 | biostudies-literature
Project description:BACKGROUND:Atopic status of the mother and maternal exposure to environmental factors are associated with increased asthma risk. Moreover, animal models demonstrate that exposure to allergens in strongly sensitized mothers influences offspring asthma development, suggesting that in utero exposures can influence offspring asthma. However, it is unclear whether maternal exposure to common human allergens such as house dust mite (HDM), in the absence of additional adjuvants, influences offspring asthma development. OBJECTIVE:We sought to determine whether maternal HDM exposure influences asthma development in offspring. METHODS:Pregnant female mice were exposed to PBS or HDM during pregnancy. Using offspring of PBS- or HDM-exposed mothers, the magnitude of HDM or Aspergillus fumigatus (AF) extract-induced airway hyperresponsiveness (AHR), airway inflammation, immunoglobulin production, TH2-associated cytokine synthesis, and pulmonary dendritic cell activity was assessed. RESULTS:Compared with offspring of PBS-exposed mothers, offspring of HDM-exposed mothers demonstrate increased AHR, airway inflammation, TH2 cytokine production, and immunoglobulin levels and a modest decrease in the phagocytic capacity of pulmonary macrophage populations following HDM exposure. Increased sensitivity to AF-induced airway disease was not observed. Offspring of HDM-exposed B-cell-deficient mothers also demonstrated increased HDM-induced AHR, suggesting that transfer of maternal immunoglobulins is not required. CONCLUSIONS:Our data demonstrate that maternal exposure to HDM during pregnancy increases asthma sensitivity in offspring in an HDM-specific manner, suggesting that vertical transmission of maternal immune responses may be involved. These findings have important implications for regulation of asthma risk, and suggest that exposure to HDM in the developed world may have underappreciated influences on the overall prevalence of allergic asthma.
| S-EPMC5550362 | biostudies-literature
Project description:House dust mite (HDM)-allergic asthma is driven by T helper 2 (Th2) lymphocytes, but also innate immune cells control key aspects of the disease. The precise function of innate natural killer (NK) cells during the initiation and propagation of asthma has been very confusing, in part because different, not entirely specific, strategies were used to target these cells. We show that HDM inhalation rapidly led to the accumulation of NK cells in the lung-draining lymph nodes and of activated CD69+ NK cells in the bronchoalveolar lumen. However, genetically engineered Ncr1-DTA or Ncr1-DTR mice that constitutively or temporarily lack NK cells, still developed all key features of acute or chronic HDM-driven asthma, such as bronchial hyperreactivity, Th2 cytokine production, eosinophilia, mucus overproduction, and Th2-dependent immunoglobulin serum titers. The same results were obtained by administration of conventional NK1.1 or asialo-GM1 NK cell-depleting antibodies, antibody-mediated blocking of the NKG2D receptor, or genetic NKG2D deficiency. Thus, although NK cells accumulate in allergen-challenged lungs, our findings comprehensively demonstrate that these cells are not required for HDM-driven asthma in the mouse.
| S-EPMC5887908 | biostudies-other
Project description:Purpose: Identify whole lung gene expression patterns modified by nanoparticle delivery of an antisense LNA/DNA oligonucleotide targeting mmu-miR145a-5p and nontargeting oligonucleotides Methods: Lung gene expression profiles of 10 week old BALB/c female mice were generated by polyA RNA-seq with Illumina HiSeq v4. Sequence reads that passed quality filters after timming were analyzed at the gene level with RNA STAR, featureCounts and Deseq2 . qRT–PCR validation was performed using TaqMan and SYBR Green methods. Results: 10-15 million sequence reads per sample were mapped to the mouse genome (build mm10). Pathway analysis of differentially expressed genes identified upregulation of gene sets for human asthma, mouse lung allergic inflammation, Muc5ac regulated genes and smooth muscle genes after allergic sensitization. Gene level exppression in each asthma-related pathway was reduced by the miR-145 antagonist. The miR-145 antagonist and several nontargeting oligos also upregulated interferon signaling pathways suggesting a general antiinflammatory effect of LNA/DNA oligos in the lung. Conclusions: Lung-directed delivery of LNA/DNA oligonucleotides with cationic lipid nanoparticles is an efffective means to prevent inflammatory gene expression in a house dust mite model of asthma
2019-02-16 | GSE126610 | GEO
Project description:DEK protein is highly expressed in asthma. However, the mechanism of DEK on mitophagy in asthma has not been fully understood. This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. PINK1-Parkin mitophagy, NLRP3 inflammasome, and apoptosis were examined after gene silencing or treatment with specific inhibitors (MitoTEMPO, MCC950, and Ac-DEVD-CHO) in house dust mite (HDM) or recombinant DEK (rmDEK)-induced WT and DEK-/- asthmatic mice and BEAS-2B cells. The regulatory role of DEK on ATAD3A was detected using ChIP-sequence and co-immunoprecipitation. rmDEK promoted eosinophil recruitment, and co-localization of TOM20 and LC3B, MFN1 and mitochondria, LC3B and VDAC, and ROS generation, reduced protein level of MnSOD in HDM induced-asthmatic mice. Moreover, rmDEK also increased DRP1 expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. These effects were partially reversed in DEK-/- mice. In BEAS-2B cells, siDEK diminished the Parkin, LC3B, and DRP1 translocation to mitochondria, mtROS, TOM20, and mtDNA. ChIP-sequence analysis showed that DEK was enriched on the ATAD3A promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models and interacted with DRP1, and siATAD3A could down-regulate DRP1 and mtDNA-mediated mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma treatment.
| S-EPMC10808738 | biostudies-literature
Project description:The increase in atopic diseases has occurred in such a short period of time that it becomes difficult to be attributed only to genetic factors, which usually need more prolonged time periods to manifest. In this setting during the last decade, the science of epigenetics has increasingly developed offering new perspectives and opening a new challenging research area. In this study we aimed to study the epigenetic patterns in B CD19+ Lymphocytes from healthy and allergic patients using the improved version of HELP assay.
2011-12-01 | GSE26080 | GEO
Project description:This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PTEN-induced putative kinase 1 (PINK1)-Parkin mediated mitophagy, NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation, and apoptosis. We found that recombinant DEK protein (rmDEK) promoted eosinophils recruitment, mitochondrial fragmentation, and outer membrane 20 (TOM20) and LC3 co-localization representing mitophagosomes in bronchoalveolar lavage fluid (BALF) in house dust mite (HDM) induced-asthma. rmDEK also reduced co-localization of mitochondrial fusion protein mitofusin1 (MFN1) and mitochondria, and the protein level of manganese superoxide dismutase (MnSOD), enhanced microtubule-associated protein1 light chain 3 (LC3) and voltage-dependent anion channels (VDAC) co-localization which also represent the mitophagosomes in airway epithelial cells, furthermore, increased dynamin-related protein 1 (DRP1) expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. In the DEK knockout mice, HDM induced asthmatic airway inflammation, MnSOD, PINK1-Parkin protein level, Parkin mediated mitophagy characterized by LC3 and Parkin co-localization in the airways, ROS generation, NLRP3 inflammation and apoptosis were fully reversed. Similar effects of rmDEK were also observed in the BEAS-2B cells, which were rescued by the autophagy inhibitor 3-MA. Moreover, DEK silencing diminished the Parkin, LC3, DRP1 translocation to mitochondria; as well as mitochondrial ROS; TOM20 and mitochondrial DNA mediated mitochondrial oxidative damage. ChIP-sequence analysis showed that DEK was enriched on the AAA domain-containing protein 3A (ATAD3A) promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models. Furthermore, ATAD3A interacted with DRP1, and knockdown of ATAD3A could down-regulate DRP1 and mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma treatment.
2023-09-24 | GSE243532 | GEO
Project description:BackgroundIL-1 receptor associated-kinase (IRAK)-M, expressed by airway epithelium and macrophages, was shown to regulate acute and chronic airway inflammation exhibiting a biphasic response in an OVA-based animal model. House dust mite (HDM) is a common real-life aeroallergen highly relevant to asthma pathogenesis. The role of IRAK-M in HDM-induced asthma remains unknown. This study was aimed to investigate the effect of IRAK-M on allergic airway inflammation induced by HDM using IRAK-M knockout (KO) mice and the potential underlying mechanisms.MethodsIRAK-M KO and wild-type (WT) mice were sensitized and challenged with HDM. The differences in airway inflammation were evaluated 24 hours after the last challenge between the two genotypes of mice using a number of cellular and molecular biological techniques. In vitro mechanistic investigation was also involved.ResultsLung expression of IRAK-M was significantly upregulated by HDM in the WT mice. Compared with the WT controls, HDM-treated IRAK-M KO mice showed exacerbated infiltration of inflammatory cells, particularly Th2 cells, in the airways and mucus overproduction, higher epithelial mediators IL-25, IL-33 and TSLP and Th2 cytokines in bronchoalveolar lavage (BAL) fluid. Lung IRAK-M KO macrophages expressed higher percentage of costimulatory molecules OX40L and CD 80 and exhibited enhanced antigen uptake. However, IRAK-M KO didn't impact the airway hyperreactivity (AHR) indirectly induced by HDM.ConclusionsThe findings indicate that IRAK-M protects allergic airway inflammation, not AHR, by modifying activation and antigen uptake of lung macrophages following HDM stimulation. Optimal regulation of IRAK-M might indicate an intriguing therapeutic avenue for allergic airway inflammation.
| S-EPMC8024803 | biostudies-literature
Project description:The efficacy of allergen immunotherapy (AIT) has been reported with different allergens including house dust mites (HDM). HDM are the most prevalent allergens in patients with asthma and/or rhinitis in China. In addition to improving symptoms, reducing medication need, and improving quality of life, AIT can change the course of allergic disease and induce allergen-specific immune tolerance. To date, the use of AIT is becoming more acceptable in China, and there are many studies about the current clinical practice immunotherapy. In this paper we discuss the main aspects of AIT undertaken in China; including symptom and medication scores, pulmonary function and airway hyperresponsiveness, specific allergen sensitivity, safety evaluation, and mechanisms underlying AIT. This review will provide some important information on AIT treatment strategies to doctors, healthcare professionals and organizations involved in the AIT in China. According to the studies in China, successful AIT may induce antibody responses and cellular reactions in relation to the significant improvement in clinical symptoms, reducing the need for medications and maintenance of stable pulmonary functions.
| S-EPMC6753424 | biostudies-literature
Project description:Evidence regarding asthma's impact on children's daily lives is limited. This prospective and cross-sectional, observational, multicenter study assessed school/work and activity impairment in children and adolescents with allergic asthma and their caregivers and allergen immunotherapy (AIT) effects. Included patients were schooled children and adolescents (5 to 17 years) with allergic asthma due to house dust mites (HDM). Impairment of school/work (i.e., absenteeism and presenteeism) and activity was measured in patients and their caregivers using the Work Productivity Impairment Questionnaire plus Classroom Impairment Questions: Allergy Specific (WPAI + CIQ:AS). HDM allergic patients with school impairment received subcutaneous AIT with a MicroCrystalline Tyrosine-associated allergoid. WPAI + CIQ:AS and effectiveness variables were compared between baseline and 1-year post-AIT. Of the 113 patients included, 59 (52.2%) and 51 (45.1%) showed school and activity impairment, respectively, missing a mean (SD) of 37.6 (24.4) % and 42.6 (25.6) % of school and activity time, respectively. Twenty-six (23%) caregivers reported activity impairment and, of the 79 (69.9%) employed, 30 (38%) reported work impairment. Of the 65 patients with school/activities impairment, 41 (63.1%) received AIT, of which 21 (51.2%) completed 1 year of treatment. Effectiveness variables and WPAI + CIQ:AS significantly improved: Mean (SD) school impairment decreased from 39.7 (26.7) to 2.1 (7.1) % (p < 0.001) and activity impairment from 46.2 (34.6) to 1.4 (3.6) % (p < 0.001).Conclusion: Allergic asthma due to HDMs results in school/work and activity impairment in children and adolescents and their caregivers. One year of AIT provided clinical benefits and reduced school and activity impairment. What is Known: • Allergic asthma impairs children's school performance and daily activities. • Allergen immunotherapy modifies allergic disease course and ameliorates its symptoms. What is New: • Asthma symptoms due to allergy to house dust mites impair children's school attendance and productivity and daily activity and their caregivers' work performance and daily lives. • Allergen immunotherapy with a house dust mite MicroCrystalline Tyrosine (MCT)-associated allergoid seems to provide clinical benefits, associated with decreased school and activity impairment, supporting it as an effective treatment option.
| S-EPMC8691866 | biostudies-literature