Gene expression profile of ovalbumin-induced lung inflammation in a murine model of asthma (original) (raw)
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The Pharmacogenomics Journal, 2006
Accumulating evidence in animal models and human asthma support a central role for IL-13 signaling in disease pathogenesis. In order to identify asthma and therapy associated genes, global transcriptional changes were monitored in mouse lung following antigen challenge (ovalbumin (OVA)), either alone or in the presence of a soluble IL-13 antagonist. Changes in whole lung gene expression after instillation of mIL-13 were also measured both in wild type and STAT6 deficient mice. A striking overlap in the gene expression profiles induced by either OVA challenge or mIL-13 was observed, further strengthening the relationship of IL-13 signaling to asthma. Consistent with results from functional studies, a subset of the OVA-induced gene expression was significantly inhibited by a soluble IL-13 antagonist while IL-13-modulated gene expression was completely attenuated in the absence of STAT6-mediated signaling. Results from these experiments greatly expand our understanding of asthma and provide novel molecular targets for therapy and potential biomarkers of IL-13 antagonism.
New asthma biomarkers: lessons from murine models of acute and chronic asthma
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2008
Many patients suffering from asthma are not fully controlled by currently available treatments, and some of them display an airway remodeling leading to exaggerated lung function decline. The aim of the present study was to unveil new mediators in asthma to better understand pathophysiology and propose or validate new potential therapeutic targets. A mouse model of asthma mimicking acute or chronic asthma disease was used to select genes undergoing a modulation in both acute and chronic conditions. Mice were exposed to ovalbumin or PBS for 1, 5, and 10 wk [short-, intermediate-, and long-term model (ST, IT, and LT)], and gene expression in the lung was studied using an Affymetrix 430 2.0 genome-wide microarray and further confirmed by RT-PCR and immunohistochemistry for selected targets. We report that 598, 1,406, and 117 genes were upregulated and 490, 153, 321 downregulated at ST, IT, and LT, respectively. Genes related to mucous secretion displayed a progressively amplified expre...
Transcriptional Regulation of Inflammatory Genes Associated with Severe Asthma
Current Pharmaceutical Design, 2011
The 10% of patients with the most severe asthma are responsible for a large part of healthcare expenditure and morbidity. Understanding the processes involved is key if new therapeutic approaches are to be developed. Evidence is accumulating that chronic diseases such as asthma are associated with temporal and spatial alterations in the pattern of inflammatory gene expression within the airways. Expression of these genes can be regulated by transcriptional, posttranscriptional, translational and epigenetic mechanisms. It is well established that binding of activated transcription factors to specific inducible gene promoter sites is tightly controlled by chromatin state as a result of histone modifications, particularly the balance between histone acetylation and deacetylation [1]. The interaction between transcription factors and the promoter is key to the diversification of gene expression in a time dependent manner leading to altered gene expression profiles. Alterations of the accessibility of transcription factors to the DNA can have residing effects upon gene transcription. This review will focus on the regulation of several groups of key genes which are involved in chronic airway inflammation and remodelling in asthma drawing mainly from our experience of studying these processes in airway smooth muscle cells. An overview is shown in
International Archives of Allergy and Immunology, 2007
Background: Asthma is a complex-trait disease caused by complicated interactions among multiple genetic and environmental risk factors. The clinical symptoms of asthma, such as periodic airway obstruction, hyperresponsiveness and mucus hypersecretion, are mediated by acute and chronic bronchial inflammation. Methods: To better understand the mechanisms by which allergen-induced acute inflammation leads to chronic asthma accompanied by irreversible airway remodeling, we analyzed time course transcriptional responses in the lungs of model mice that were exposed to aerosolized ovalbumin for up to 9 weeks after an initial sensitization. Results: We observed increased levels of total plasma IgE and histological changes in lung tissues from the ovalbumin-treated mice, which is consistent with the typical inflammatory phenotypes of asthma pathogenesis. Our oligonucleotide microarray analyses revealed a total of 776 differentially expressed genes induced by antigenic challenge (≧1.5-fold ch...
Gene expression profiling in human asthma
Proceedings of the American Thoracic Society, 2007
Asthma is a chronic inflammatory disease of the lungs, characterized by airway hyperreactivity, mucus hypersecretion, and airflow obstruction. Despite recent advances, the genetic regulation of asthma pathogenesis is still largely unknown. Gene expression profiling techniques are well suited to study complex diseases and hold substantial promise for identifying novel genes and pathways in asthma; however, relatively few studies have been completed in human asthma. The few studies that have been done have identified many novel candidate genes and pathways in asthma pathogenesis, including ALOX15 and serine proteinase inhibitors cathepsin C and G. The interpretation of results of these studies should be cautious, as limitations include small sample sizes and heterogeneity of study populations and tissues sampled. In the future, the promise of gene expression studies would be enhanced by the use of larger sample sizes and attempts to standardize phenotype, sample collection techniques,...
Generation of IL10 and TGFB1 coexpressed mice displaying resistance to ovalbumin-induced asthma
Transgenic research, 2016
Asthma is a common chronic inflammatory disease in the airways with wide prevalence, and it is thought to be caused by the combinational factors in environment and genetics. A large body of studies has suggested that cell immunity played a vital role in regulating the airway hyperreactivity (AHR) and inflammation. Therefore, we here developed a mouse model of asthma by microinjecting the pronucleus with a vector spontaneously coding human IL10 and TGFB1 gene to explore the possible interaction between these two potent molecules during asthma progression. From the total 35 newborn mice, we successfully obtained 3 founders expressing exogenous genes. In the transgenic mice, we observed profoundly enhanced expression of IL10 and TGFB1. In the condition of ovalbumin challenge, transgenic mice displayed a 1.9-fold higher MCh50 score than wild-type counterparts, indicating reminiscent AHR. Meanwhile, a three-fold decrease of cell counts in bronchoalveolar lavage fluid (BALF) was recorded ...
The Clinical and Environmental Determinants of Airway Transcriptional Profiles in Allergic Asthma
American Journal of Respiratory and Critical Care Medicine, 2012
Rationale: Gene expression profiling of airway epithelial and inflammatory cells can be used to identify genes involved in environmental asthma. Methods: Airway epithelia and inflammatory cells were obtained via bronchial brush and bronchoalveolar lavage (BAL) from 39 subjects comprising three phenotypic groups (nonatopic nonasthmatic, atopic nonasthmatic, and atopic asthmatic) 4 hours after instillation of LPS, house dust mite antigen, and saline in three distinct subsegmental bronchi. RNA transcript levels were assessed using whole genome microarrays. Measurements and Main Results: Baseline (saline exposure) differences in gene expression were related to airflow obstruction in epithelial cells (C3, ALOX5AP, CCL18, and others), and to serum IgE (innate immune genes and focal adhesion pathway) and allergic-asthmatic phenotype (complement genes, histone deacetylases, and GATA1 transcription factor) in inflammatory cells. LPS stimulation resulted in pronounced transcriptional response across all subjects in both airway epithelia and BAL cells, with strong association to nuclear factor-kB and IFNinducible genes as well as signatures of other transcription factors (NRF2, C/EBP, and E2F1) and histone proteins. No distinct transcriptional profile to LPS was observed in the asthma and atopy phenotype. Finally, although no consistent expression changes were observed across all subjects in response to house dust mite antigen stimulation, we observed subtle differences in gene expression (e.g., GATA1 and GATA2) in BAL cells related to the asthma and atopy phenotype. Conclusions: Our results indicate that among individuals with allergic asthma, transcriptional changes in airway epithelia and inflammatory cells are influenced by phenotype as well as environmental exposures.
Pathways activated during human asthma exacerbation as revealed by gene expression patterns in blood
PloS one, 2011
Asthma exacerbations remain a major unmet clinical need. The difficulty in obtaining airway tissue and bronchoalveolar lavage samples during exacerbations has greatly hampered study of naturally occurring exacerbations. This study was conducted to determine if mRNA profiling of peripheral blood mononuclear cells (PBMCs) could provide information on the systemic molecular pathways involved during asthma exacerbations.
Inflammation Research, 2009
Objective To investigate whether challenge with increasing allergen doses could differently affect allergeninduced airway hyperresponsiveness (AHR) and inflammatory cell accumulation in mouse model of asthma, providing an experimental model to investigate their relationship. Material and methods AHR and accumulation of inflammatory cells in bronchoalveolar lavage fluid (BALF) and into the lungs were compared in ovalbumin-sensitized mice that were challenged intranasally with 2.5, 10, 25 or 100 lg of ovalbumin/mouse. Results Both AHR and inflammatory cell accumulation were proportional to the ovalbumin dose used for challenge. However, in group challenged with 10 lg of ovalbumin airway inflammation was present, although allergen-induced AHR was not detected. Additional analysis indicated that neither mucous hyperproduction nor eosinophil degranulation could be correlated to presence of AHR in this model, whereas concentration of interleukin (IL)-13 in BALF was increased only in those groups in which AHR was present. Conclusions Altogether, intranasal challenge of mice with increasing allergen doses could serve as a suitable experimental system for investigation of mechanisms by which airway inflammation leads to allergen-induced AHR. Our initial findings are in line with previous reports that dissociate AHR from amount of eosinophil accumulation and imply the role of IL-13 in this process. Keywords Airway hyperresponsiveness Á Allergen dose Á Asthma Á Eosinophils Á Mice Abbreviations AHR Airway hyperresponsiveness BALF Bronchoalveolar lavage fluid EPO Eosinophil peroxidase IL Interleukin PAS Periodic acid-Schiff SEM Standard error of the mean Responsible Editor: A. Falus.