Statin Immuno-Metabolomics in Asthma (part I)
Ontology highlight
ABSTRACT:
ORGANISM(S): Macaca Mulatta
TISSUE(S): Lung
DISEASE(S): Asthma
PROVIDER: ST000843 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
Dataset's files
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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.
2022-06-09 | PXD033172 | Pride
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2024-05-01 | PXD051921 | Pride
Project description:ObjectivesWe hypothesised that severe asthmatics taking a statin drug, in addition to inhaled corticosteroids/long-acting ?-agonist inhaler therapy, would have better asthma symptom control and improved lung function compared to their controls.Study designA retrospective, cross-sectional study of 165 patients with severe asthma seen from 2001-2008. Hierarchical linear and logistic regression models were used for modelling fitting.SettingUniversity of California, Davis Medical Center (Sacramento, California, USA). Academic, single-centre, severe asthma subspecialty clinic.Participants612 screened, 223 eligible and 165 adult patients were included in the final study (N=165; 31 statin users and 134 non-users).Primary and secondary outcome measuresThe primary endpoint was asthma control as measured by the Asthma Control Test (ACT). The secondary endpoints included lung function, symptoms and the need for corticosteroid burst and peripheral eosinophil count.ResultsAt baseline, statin users compared to non-users were older, had lower lung function (FEV1% predicted, FEV1, forced vital capacity and FEF25-75%) and had a higher prevalence of comorbid conditions. Statin use was associated with more aspirin and ipratropium inhaler use than in non-users. Patients in both groups were obese (body mass index ? 30). Statin users had better asthma symptom control compared to non-users (higher adjusted mean ACT score by 2.2±0.94 points, p<0.02). Median statin use was for 1 year. There were no statistically significant differences in lung function, corticosteroid or rescue bronchodilator use or peripheral eosinophilia between the two groups.ConclusionsIn our severe asthma referral population, statin users already taking inhaled controller therapy achieved better asthma control compared to non-users. The implications of this study is that patients with severe asthma could potentially benefit from added statin treatment. Because our study population was on average obese, the obese severe asthmatic may be a viable asthma subphenotype for further studies. Prospective randomised clinical trials evaluating the safety and efficacy of statins in severe asthma are warranted.
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Project description:Viral-induced severe asthma exacerbations in children are characterized by IRF7hi and IRF7lo molecular phenotypes. We have developed an experimental animal model that mirrors these response patterns in asthma-resistant PVG and asthma-susceptible BN rats respectively. We aimed to i) characterize the immunological and molecular hallmarks of PVG and BN responses to virus/allergen exposure, and (ii) evaluate the utility of innate immune training with the bacterial lysate OM85 to attenuate ensuing inflammation. Animals were sensitized to OVA/alum, inoculated with murine-adapted Rhinovirus model (vMC0), and challenged with OVA 24h later. RNA-seq was performed on lung and bone marrow at several time points post virus/allergen exposure.
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Project description:BackgroundMild equine asthma (MEA) and severe equine asthma (SEA) are two of the most frequent equine airway inflammatory diseases, but knowledge about their pathogenesis is limited. The goal of this study was to investigate gene expression differences in the respiratory tract of MEA- and SEA-affected horses and their relationship with clinical signs.MethodsClinical examination and endoscopy were performed in 8 SEA- and 10 MEA-affected horses and 7 healthy controls. Cytological and microbiological analyses of bronchoalveolar lavage (BAL) fluid were performed. Gene expression profiling of BAL fluid was performed by means of a custom oligo-DNA microarray.ResultsIn both MEA and SEA, genes involved in the genesis, length, and motility of respiratory epithelium cilia were downregulated. In MEA, a significant overexpression for genes encoding inflammatory mediators was observed. In SEA, transcripts involved in bronchoconstriction, apoptosis, and hypoxia pathways were significantly upregulated, while genes involved in the formation of the protective muco-protein film were underexpressed. The SEA group also showed enrichment of gene networks activated during human asthma.ConclusionsThe present study provides new insight into equine asthma pathogenesis, representing the first step in transcriptomic analysis to improve diagnostic and therapeutic approaches for this respiratory disease.
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Project description:Several reports have shown that statin treatment benefits patients with asthma; however, inconsistent effects have been observed. The mir-152 family (148a, 148b and 152) has been implicated in asthma. These microRNAs suppress HLA-G expression, and rs1063320, a common SNP in the HLA-G 3'UTR that is associated with asthma risk, modulates miRNA binding. We report that statins upregulate mir-148b and 152, and affect HLA-G expression in an rs1063320-dependent fashion. In addition, we found that individuals who carried the G minor allele of rs1063320 had reduced asthma-related exacerbations (emergency department visits, hospitalizations or oral steroid use) compared with non-carriers (P=0.03) in statin users ascertained in the Personalized Medicine Research Project at the Marshfield Clinic (n=421). These findings support the hypothesis that rs1063320 modifies the effect of statin benefit in asthma, and thus may contribute to variation in statin efficacy for the management of this disease.
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