Dataset Information

Lung gene expression in a rhesus allergic asthma model correlates with physiologic parameters of disease and exhibits common and distinct pathways with human asthma and a mouse asthma model.

ABSTRACT: Experimental nonhuman primate models of asthma exhibit multiple features that are characteristic of an eosinophilic/T helper 2 (Th2)-high asthma subtype, characterized by the increased expression of Th2 cytokines and responsive genes, in humans. Here, we determine the molecular pathways that are present in a house dust mite-induced rhesus asthma model by analyzing the genomewide lung gene expression profile of the rhesus model and comparing it with that of human Th2-high asthma. We find that a prespecified human Th2 inflammation gene set from human Th2-high asthma is also present in rhesus asthma and that the expression of the genes comprising this gene set is positively correlated in human and rhesus asthma. In addition, as in human Th2-high asthma, the Th2 gene set correlates with physiologic markers of allergic inflammation and disease in rhesus asthma. Comparison of lung gene expression profiles from human Th2-high asthma, the rhesus asthma model, and a common mouse asthma model indicates that genes associated with Th2 inflammation are shared by all three species. However, some pathophysiologic aspects of human asthma (ie, subepithelial fibrosis, angiogenesis, neural biology, and immune host defense biology) are better represented in the gene expression profile of the rhesus model than in the mouse model. Further study of the rhesus asthma model may yield novel insights into the pathogenesis of human Th2-high asthma.

SUBMITTER: Abbas AR

PROVIDER: S-EPMC3181391 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Lung gene expression in a rhesus allergic asthma model correlates with physiologic parameters of disease and exhibits common and distinct pathways with human asthma and a mouse asthma model.

Abbas Alexander R AR Jackman Janet K JK Bullens Sherron L SL Davis Sarah M SM Choy David F DF Fedorowicz Grazyna G Tan Martha M Truong Bao-Tran BT Gloria Meng Y Y Diehl Lauri L Miller Lisa A LA Schelegle Edward S ES Hyde Dallas M DM Clark Hilary F HF Modrusan Zora Z Arron Joseph R JR Wu Lawren C LC

The American journal of pathology 20110803 4

Experimental nonhuman primate models of asthma exhibit multiple features that are characteristic of an eosinophilic/T helper 2 (Th2)-high asthma subtype, characterized by the increased expression of Th2 cytokines and responsive genes, in humans. Here, we determine the molecular pathways that are present in a house dust mite-induced rhesus asthma model by analyzing the genomewide lung gene expression profile of the rhesus model and comparing it with that of human Th2-high asthma. We find that a p ...[more]

PMID: 21819959

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Project description:BACKGROUND:Asthma is a chronic airway disease affecting millions of people. Better methods to define asthma subgroups using clinical parameters and molecular biomarkers are crucial in the development of personalized medicine. OBJECTIVE:The aim of this study was to determine if circulating microRNAs (miRNAs) may be used to distinguish well-defined asthma groups. METHODS:Blood serum from 116 well-defined subjects, including healthy controls and individuals with allergic or non-allergic asthma, from the West Sweden Asthma Study were included. Serum was analyzed for circulating miRNA expression of miR-126, -?145, -146a, -?155, -?223, and -374a and eosinophil cationic protein (ECP). Correlations between clinical characteristics and circulating miRNA expression as well as potential miRNA gene targets were investigated. RESULTS:A subset of miRNAs were differentially expressed between allergic and non-allergic asthmatic individuals. Alterations in expression of miR-155, -146a, -374a and?-?145 were observed in allergic asthmatics in response to inhaled corticosteroid usage. Additionally, miR-223 and miR-374a expression varied in non-allergic asthmatics based on blood eosinophil numbers. Numerous clinical parameters, including lung function measurements, correlated with subsets of miRNAs. Finally, pathway analysis revealed a potential role for inhaled corticosteroid induced miRNAs in leukocyte regulation, IL-6 signaling and glucocorticoid response. CONCLUSION:Circulating miRNA expression was altered in subjects with allergic and non-allergic asthma and correlated to clinical parameters including lung function and potential gene targets involved in immune processes. This combination of clinical and molecular data may be a basis for the further, more precise classification of asthma subgroups. Taken together, these findings would further asthma research and benefit future patients through the discovery of molecular mechanisms as well as identifying asthma subgroups contributing to the development of personalized medicine.

Project description:Allergic asthma is characterized by airway eosinophilia, increased mucin production and allergen-specific IgE. Fc gamma receptor IIb (FcgammaRIIb), an inhibitory IgG receptor, has recently emerged as a negative regulator of allergic diseases like anaphylaxis and allergic rhinitis. However, no studies to date have evaluated its role in allergic asthma. Our main objective was to study the role of FcgammaRIIb in allergic lung inflammation. We used a murine model of allergic airway inflammation. Inflammation was quantified by BAL inflammatory cells and airway mucin production. FcgammaRIIb expression was measured by qPCR and flow cytometry and the cytokines were quantified by ELISA. Compared to wild type animals, FcgammaRIIb deficient mice mount a vigorous allergic lung inflammation characterized by increased bronchoalveolar lavage fluid cellularity, eosinophilia and mucin content upon ragweed extract (RWE) challenge. RWE challenge in sensitized mice upregulated FcgammaRIIb in the lungs. Disruption of IFN-gamma gene abrogated this upregulation. Treatment of naïve mice with the Th1-inducing agent CpG DNA increased FcgammaRIIb expression in the lungs. Furthermore, treatment of sensitized mice with CpG DNA prior to RWE challenge induced greater upregulation of FcgammaRIIb than RWE challenge alone. These observations indicated that RWE challenge upregulated FcgammaRIIb in the lungs by IFN-gamma- and Th1-dependent mechanisms. RWE challenge upregulated FcgammaRIIb on pulmonary CD14+/MHC II+ mononuclear cells and CD11c+ cells. FcgammaRIIb deficient mice also exhibited an exaggerated RWE-specific IgE response upon sensitization when compared to wild type mice. We propose that FcgammaRIIb physiologically regulates allergic airway inflammation by two mechanisms: 1) allergen challenge mediates upregulation of FcgammaRIIb on pulmonary CD14+/MHC II+ mononuclear cells and CD11c+ cells by an IFN-gamma dependent mechanism; and 2) by attenuating the allergen specific IgE response during sensitization. Thus, stimulating FcgammaRIIb may be a therapeutic strategy in allergic airway disorders.

Dataset Information

Lung gene expression in a rhesus allergic asthma model correlates with physiologic parameters of disease and exhibits common and distinct pathways with human asthma and a mouse asthma model.

Publications

Lung gene expression in a rhesus allergic asthma model correlates with physiologic parameters of disease and exhibits common and distinct pathways with human asthma and a mouse asthma model.

Similar Datasets

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