In utero allergen exposure reprograms primary developmental patterns of lung gene expression and influences respiratory phenotype in rat models of asthma susceptibility.
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE32622 | GEO | 2012/10/11
SECONDARY ACCESSION(S): PRJNA147139
REPOSITORIES: GEO
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Project description:Transcriptome of whole lung of rat from 3 genetic strains, 3 postnatal time points and 2 exposures (saline versus ovalbumin) in (mainly) 4 replicate measurements per condition. Total RNA obtained from whole lung of rat from 3 genetic strains, 3 postnatal time points and 2 exposures (saline versus ovalbumin) in (mainly) 4 replicate measurements per condition.
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Project description:Asthma is a complex syndrome associated with episodic decompensations provoked by aeroaller-gen exposures. The underlying pathophysiological states driving exacerbations are latent in the resting state and do not adequately inform biomarker-driven therapy. A better understanding of the pathophysiological pathways driving allergic exacerbations is needed. We hypothesized that disease-associated pathways could be identified in humans by unbiased metabolomics of bron-choalveolar fluid (BALF) during the peak inflammatory response provoked by a bronchial aller-gen challenge. We analyzed BALF metabolites in samples from 12 volunteers who underwent segmental bronchial antigen provocation (SBP-Ag). Metabolites were quantified using liquid chromatography-tandem mass spectrometry (LC–MS/MS) followed by pathway analysis and cor-relation with airway inflammation. SBP-Ag induced statistically significant changes in 549 fea-tures that mapped to 72 uniquely identified metabolites. From these features, two distinct induci-ble metabolic phenotypes were identified by the principal component analysis, partitioning around medoids (PAM) and k-means clustering. Ten index metabolites were identified that in-formed the presence of asthma-relevant pathways, including unsaturated fatty acid produc-tion/metabolism, mitochondrial beta oxidation of unsaturated fatty acid, and bile acid metabolism. Pathways were validated using proteomics in eosinophils. A segmental bronchial allergen chal-lenge induces distinct metabolic responses in humans, providing insight into pathogenic and pro-tective endotypes in allergic asthma.
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Project description:BackgroundExposure to traffic pollution particulate matter, predominantly diesel exhaust particles (DEPs), increases the risk of asthma and asthma exacerbation; however, the underlying mechanisms remain poorly understood.ObjectiveWe sought to examine the effect of DEP exposure on the generation and persistence of allergen-specific memory T cells in asthmatic patients and translate these findings by determining the effect of early DEP exposure on the prevalence of allergic asthma in children.MethodsThe effect of DEPs on house dust mite (HDM)-specific memory responses was determined by using an asthma model. Data from children enrolled in the Cincinnati Childhood Allergy and Air Pollution Study birth cohort were analyzed to determine the effect of DEP exposure on asthma outcomes.ResultsDEP coexposure with HDM resulted in persistent TH2/TH17 CD127(+) effector/memory cells in the lungs, spleen, and lymph nodes of adult and neonatal mice. After 7 weeks of rest, a single exposure to HDM resulted in airway hyperresponsiveness and increased TH2 cytokine levels in mice that had been previously exposed to both HDM and DEPs versus those exposed to HDM alone. On the basis of these data, we examined whether DEP exposure was similarly associated with increased asthma prevalence in children in the presence or absence of allergen exposure/sensitization in the Cincinnati Childhood Allergy and Air Pollution Study birth cohort. Early-life exposure to high DEP levels was associated with significantly increased asthma prevalence among allergic children but not among nonallergic children.ConclusionThese findings suggest that DEP exposure results in accumulation of allergen-specific TH2/TH17 cells in the lungs, potentiating secondary allergen recall responses and promoting the development of allergic asthma.
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Project description:In recent years, alveolar macrophages (AM) have been shown to play an important role in environmental allergen-induced airway inflammation in asthma. In this study, we investigated the effect of house dust mite (HDM) and lipopolysaccharide (LPS) challenge on the transcriptome of AM from patients with mild asthma. We have shown previously that intrabronchial HDM/LPS challenge induces a mixed eosinophilic and neutrophil airways inflammation in asthma patients(5). Therefore, we hypothesize that exposure of AM to HDM/LPS would upregulate genes associated with eosinophil and neutrophil signaling. AM were harvested from the bronchoalveolar fluid of 8 asthma patients who were challenged with either saline in one lung segment or HDM/LPS in the contralateral lung segment. We performed RNA sequencing and found over 1000 significantly different expressed genes following HDM/LPS challenge. To the best of our knowledge, this is the first investigation to examine gene expression profiles in AM from asthma patients challenged with HDM and LPS in vivo. Using a well-controlled study design allowing paired analysis of saline and HDM/LPS effects in the same patient, we identified different transcriptional profiles in AM as consequence of local exposure to HDM and LPS. These findings may provide a better understanding of AM functions in (exacerbations of) allergic asthma.
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Project description:Experimental asthma was induced in BALB/c mice by sensitization and challenge with the allergen ovalbumin. Control groups received PBS. To investigate the innate immune component of experimental asthma, we also analyzed recombinase activating gene (RAG) deficient mice following exposure to ovalbumin and control PBS Keywords: case control
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Project description:Asthma is the leading serious pediatric chronic illness in the United States, affecting 7.1 million children. The prevalence of asthma in children under 4 years of age has increased dramatically in the last 2 decades. Existing evidence suggests that this increase in prevalence derives from early environmental exposures acting on a pre-existing asthma-susceptible genotype. We studied the origins of asthma susceptibility in developing lung in rat strains that model the distinct phenotypes of airway hyperresponsiveness (Fisher rats) and atopy (brown Norway [BN] rats). Postnatal BN rat lungs showed increased epithelial proliferation and tracheal goblet cell hyperplasia. Fisher pups showed increased lung resistance at age 2 weeks, with elevated neutrophils throughout the postnatal period. Diverse transcriptomic signatures characterized the distinct respiratory phenotypes of developing lung in both rat models. Linear regression across age and strain identified developmental variation in expression of 1,376 genes, and confirmed both strain and temporal regulation of lung gene expression. Biological processes that were heavily represented included growth and development (including the T Box 1 transcription factor [Tbx5], the epidermal growth factor receptor [Egfr], the transforming growth factor beta-1-induced transcript 1 [Tgfbr1i1]), extracellular matrix and cell adhesion (including collagen and integrin genes), and immune function (including lymphocyte antigen 6 (Ly6) subunits, IL-17b, Toll-interacting protein, and Ficolin B). Genes validated by quantitative RT-PCR and protein analysis included collagen III alpha 1 Col3a1, Ly6b, glucocorticoid receptor and Importin-13 (specific to the BN rat lung), and Serpina1 and Ficolin B (specific to the Fisher lung). Innate differences in patterns of gene expression in developing lung that contribute to individual variation in respiratory phenotype are likely to contribute to the pathogenesis of asthma.
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Project description:Allergen exposure was thought to play a critical role in the etiology of AR. And allergen avoidance, the practice of avoiding exposure to allergens, has been generally advised as the management of AR. However, the effect is uncertain and the underlying mechanism is far from known. We used gene expression microarrays to identify genes differentially regulated by allergen avoidance in allergic rhinitis mouse model. Affymetrix Mouse Gene 1.0 ST arrays were used to identify the expression profiling of nasal mucosa in three groups of mice: (1) mice sensitized and challenged with saline (control group); (2) mice sensitized and challenged with ovalbumin (OVA) and sacrificed 2 hours after the last challenge (OVA group); (3) mice sensitized and challenged with OVA and sacrificed 4 weeks after the last challenge (4w-after group).
2013-11-28 | E-GEOD-52804 | biostudies-arrayexpress
Project description:BackgroundChildhood asthma prevalence and morbidity varies among Latinos in the United States, with Puerto Ricans having the highest and Mexicans the lowest.ObjectiveTo determine whether genetic ancestry is associated with the odds of asthma among Latinos, and secondarily whether genetic ancestry is associated with lung function among Latino children.MethodsWe analyzed 5493 Latinos with and without asthma from 3 independent studies. For each participant, we estimated the proportion of African, European, and Native American ancestry using genome-wide data. We tested whether genetic ancestry was associated with the presence of asthma and lung function among subjects with and without asthma. Odds ratios (OR) and effect sizes were assessed for every 20% increase in each ancestry.ResultsNative American ancestry was associated with lower odds of asthma (OR = 0.72, 95% CI: 0.66-0.78, P = 8.0 × 10(-15)), while African ancestry was associated with higher odds of asthma (OR = 1.40, 95% CI: 1.14-1.72, P = .001). These associations were robust to adjustment for covariates related to early life exposures, air pollution, and socioeconomic status. Among children with asthma, African ancestry was associated with lower lung function, including both pre- and post-bronchodilator measures of FEV1 (-77 ± 19 mL; P = 5.8 × 10(-5) and -83 ± 19 mL; P = 1.1 x 10(-5), respectively) and forced vital capacity (-100 ± 21 mL; P = 2.7 × 10(-6) and -107 ± 22 mL; P = 1.0 x 10(-6), respectively).ConclusionDifferences in the proportions of genetic ancestry can partially explain disparities in asthma susceptibility and lung function among Latinos.
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