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Murine Pulmonary Responses to Ambient Baltimore Particulate Matter

ABSTRACT: Murine Pulmonary Responses to Ambient Baltimore Particulate Matter: Genomic Analysis and Contribution to Airway Hyperresponsiveness Asthma is a complex disease characterized by airway hyperresponsiveness (AHR) and chronic airway inflammation. Environmental factors such as ambient particulate matter (PM), a major air pollutant, has been demonstrated in epidemiological studies to contribute to asthma exacerbation and increased asthma prevalence. OBJECTIVE: We investigated the genomic and pathophysiological effects of Baltimore PM (median diameter 1.78 µm) in a murine model of asthma to identify potential biomarkers. METHODS: A/J mice with ovalbumin (OVA) –induced AHR were exposed to PM (20 mg/kg, intratracheal), and both AHR and bronchoalveolar lavage (BAL) were assayed on days 1, 4, and 7 post exposure. Lung gene expression profiling (Affymetrix Mouse430_ 2.0) by PM (20 mg/kg, intratracheal) were assayed on OVA- and / or PM--challenged mice. RESULTS: Significant increases of airway responsiveness in OVA-treated mice were observed, indicating an asthmatic phenotype. Ambient PM exposure induced significant changes in AHR in both naive mice and OVA-induced asthmatic mice. In both naive and OVA challenged asthmatic mice, PM induced eosinophil and neutrophil infiltration into airways, elevated BAL protein content, and stimulated secretion of TH1 cytokines (IFN-g, IL-6, and TNF-a) and TH2 cytokines (IL-4, IL-5, and eotaxin) into BAL. Consistent with these results, PM induced expression of genes of innate immune response, chemotaxis and complementary system. CONCLUSION: These studies, consistent with epidemiological data, indicate that PM increases AHR and lung inflammation in naïve mice and exacerbates the asthma phenotype of increased AHR and gene expression pattern changes correlated with acute lung inflammation and airway damage. We used microarrays to detail the global programme of gene expression induced by rhPBEF treatment and VALI. Keywords: gene expression

ORGANISM(S): Mus musculus

PROVIDER: GSE9465 | GEO | 2007/12/01

SECONDARY ACCESSION(S): PRJNA103235

REPOSITORIES: GEO

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Project description:Murine Pulmonary Responses to Ambient Baltimore Particulate Matter: Genomic Analysis and Contribution to Airway Hyperresponsiveness; Asthma is a complex disease characterized by airway hyperresponsiveness (AHR) and chronic airway inflammation. Environmental factors such as ambient particulate matter (PM), a major air pollutant, has been demonstrated in epidemiological studies to contribute to asthma exacerbation and increased asthma prevalence. OBJECTIVE: We investigated the genomic and pathophysiological effects of Baltimore PM (median diameter 1.78 Âµm) in a murine model of asthma to identify potential biomarkers. METHODS: A/J mice with ovalbumin (OVA) âinduced AHR were exposed to PM (20 mg/kg, intratracheal), and both AHR and bronchoalveolar lavage (BAL) were assayed on days 1, 4, and 7 post exposure. Lung gene expression profiling (Affymetrix Mouse430_ 2.0) by PM (20 mg/kg, intratracheal) were assayed on OVA- and / or PM--challenged mice. RESULTS: Significant increases of airway responsiveness in OVA-treated mice were observed, indicating an asthmatic phenotype. Ambient PM exposure induced significant changes in AHR in both naive mice and OVA-induced asthmatic mice. In both naive and OVA challenged asthmatic mice, PM induced eosinophil and neutrophil infiltration into airways, elevated BAL protein content, and stimulated secretion of TH1 cytokines (IFN-g, IL-6, and TNF-a) and TH2 cytokines (IL-4, IL-5, and eotaxin) into BAL. Consistent with these results, PM induced expression of genes of innate immune response, chemotaxis and complementary system. CONCLUSION: These studies, consistent with epidemiological data, indicate that PM increases AHR and lung inflammation in naÃ¯ve mice and exacerbates the asthma phenotype of increased AHR and gene expression pattern changes correlated with acute lung inflammation and airway damage. We used microarrays to detail the global programme of gene expression induced by rhPBEF treatment and VALI. Experiment Overall Design: animals were treated by PBS, Oval albumin, PM, or both OVA/PM

Project description:Background: Several studies indicate that asthma is a polygenic disease, and its complexity originates from the interaction of an unknown number of genes with environmental factors. Objective: In this study we aimed to identify new genes, gene groups and pathways involved in the pathogenesis of experimental asthma. Methods: In an ovalbumin-induced murine model of asthma we applied microarray gene expression analysis of the lung at different time points in the asthmatic process. Advanced statistical methods were used to relate gene expression changes to cellular processes and to integrate our results into multiple levels of information available in public databases. Results: According to the observed marked neutrophil infiltration found early, at 4 hours after the first allergen challenge, gene expression pattern reflected mainly an acute inflammatory response and strong chemotactic activity. At 24 hours after the third allergen challenge, gene set enrichment analysis revealed significant overrepresentation of gene sets corresponding to Th2 type inflammation models. Among the top downregulated transcripts, an antioxidant enzyme, paraoxonase-1 (PON1) was identified. Reduced PON1 protein expression in the lung was confirmed by immunohistochemical analysis. In human asthmatic patients we found that serum PON1 activity was reduced at exacerbation, but increased parallel with improving asthma symptoms. PON1 gene polymorphisms did not influence the susceptibility to the disease. Conclusion: Our observations suggest that an altered PON1 activity might be involved in the pathogenesis of asthma, and PON1 might be a potential new therapeutic target as well as a new diagnostic tool for following up the effect of therapy. Experiment Overall Design: Experimental design: Experiment Overall Design: Three groups of mice (6 mice/group) were sensitized and challenged with allergen (OVA), one group (control group) was sensitized and challenged with placebo (PBS) and served as a control. On day 28 and 30, 4 h after the first and third allergen challenge, mice in groups 1 and 2 were anaesthetized by an intraperitoneal injection of ketamine and xylazine, BAL was isolated and the lungs were removed for further analysis. On day 31, 24h after the third (last) allergen challenge mice in group 3 and the controls were anaesthetized, and airway hyper-responsiveness (AHR) was assessed. After the AHR measurements, BAL sampling and lung tissue collection were performed, the same way as it was carried out in groups 1 and 2. Cellular composition of BAL, and lung histology were examined in all mice in all groups. AHR was measured in controls and group 3 on day 31. 1000 ng-1000 ng quality-checked total lung tissue RNA samples from OVA sensitized and challenged mice from group 1, 2 and 3 were identically labeled with Cy5 dye, while lung tissue RNA samples from group 4 (control, placebo sensitized and challenged) were pooled and labeled with Cy3 dye, and served as a common reference.

Project description:Ethnopharmacological relevance: Gubenfangxiao decoction (GBFXD) is a traditional Chinese medicine formula derived from Yupingfensan, an ancient formula widely used to treat respiratory diseases such as repeated respiratory infection, allergic rhinitis, bronchitis, and asthma. In recent years, GBFXD has been applied to efficaciously and safely treat asthma. However, the mechanism of GBFXD is still not fully elucidated. Aim of the study: A label-free proteomic method was to employed to explore the protective mechanism of GBFXD in respiratory syncytial virus (RSV)-ovalbumin (OVA)-induced chronic persistent asthmatic mice. Materials and methods: After RSV-OVA challenge, mice were orally administered GBFXD at a dose of 36 g/kg/d accompanied with OVA nasal spray once every 3 days for 28 days. The label-free proteomics-based liquid chromatography-tandem mass spectrometry method was used to explore the differentially abundant proteins (DAPs) in the serum from model mice compared with that in control mice (M:C), and in GBFXD-treated mice compared with that in model mice (G:M). We utilized OmicsBean (http://www.omicsbean.cn), a multi-omics data analysis platform, to perform bioinformatics analysis of DAPs. Enzyme-linked immunosorbent assay and Western Blotting were performed to measure the levels of related proteins and verify the results of proteomics analysis. Results: A total of 69 significant DAPs were identified including 39 in M:C, 46 in G:M, and 16 common differential proteins. Bioinformatics analysis revealed that the DAPs of M:C were mainly involved in inflammatory response and were related to lipid metabolism. However, the DAPs of G:M mostly participated in stress response, inflammatory response, and epithelial cell proliferation. Serum levels of Apoa-1, Apoc-1, Cfd, and Lrg1, EGFR and Lrg1 in the lungs were consistent with the results of proteomic analysis. Apoa-1 and Apoc-1 are closely related to cholesterol transport, lipid metabolism balance, and airway epithelial integrity; Cfd participates in immune response, affecting the occurrence and development of inflammation; EGFR and Lrg1 are involved in epithelial cell proliferation, influencing the process of airway remodeling. Conclusions: GBFXD may affect inflammatory and immune responses of asthma by regulating cholesterol transport and complement factor activation. Furthermore, it could repair damaged airway epithelium and avoid airway remodeling to prevent and treat asthma.

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Murine Pulmonary Responses to Ambient Baltimore Particulate Matter

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