A Functional and Regulatory Map of Asthma

Abstract

The prevalence and morbidity of asthma, a chronic inflammatory airway disease, is increasing. Animal models provide a meaningful but limited view of the mechanisms of asthma in humans. A systemslevel view of asthma that integrates multiple levels of molecular and functional information is needed. For this, we compiled a gene expression compendium from five publicly available mouse microarray datasets and a gene knowledge base of 4,305 gene annotation sets. Using this collection we generated a high-level map of the functional themes that characterize animal models of asthma, dominated by innate and adaptive immune response. We used Module Networks analysis to identify co-regulated gene modules. The resulting modules reflect four distinct responses to treatment, including early response, general induction, repression, and IL-13-dependent response. One module with a persistent induction in response to treatment is mainly composed of genes with suggested roles in asthma, suggesting a similar role for other module members. Analysis of IL-13-dependent response using protein interaction networks highlights a role for TGF-b1 as a key regulator of asthma. Our analysis demonstrates the discovery potential of systems-level approaches and provides a framework for applying such approaches to asthma.Keywords: house dust mite; IL-13; ovalbumin; systems biology; TGF-b Asthma is a chronic lung disease characterized by airway inflammation, hyperresponsiveness, remodeling, and obstruction (1). The lung phenotype in asthma is believed to be determined by the interaction of the environment with the patient's genetic background (2). This interaction leads to a dramatic change in the airway microenvironment that includes activation of inflammatory pathways, recruitment of immune cells that are not usually present in the airway, and a dramatic change in the phenotype of airway resident cells. While individual changes in many of these factors may generate components of the asthmatic phenotype, it is the converging effects of these pathways on recruited and altered cells that determine the patient's disease.The advent of high-throughput technologies for gene and protein profiling has greatly improved our ability to characterize the behavior of genes and proteins in health and disease. Using animal models of allergic airway disease, investigators applied DNA microarrays to identify potential regulators of asthmatic airway inflammation such as C5 (3), ARG1 (4), ADAM8 (5), SPRR2 (6) as well as to explore the pathways activated by IL13 and STAT6 during the development of allergen-induced lung inflammation (7-9). Transcriptional analysis of the response to IL-13, allergen challenge, syncytial virus infection, and corticosteroids in epithelial cells identified multiple and rarely overlapping genes (10-14). While many of these studies used elegant experimental approaches to dissect pathways and to identify and validate potential novel key regulatory molecules, the majority of their insights were obtained using statistical methods that select...

Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation

“…We chose a pan-MMP sensor for imaging of enzyme burden because the disease mobilizes multiple MMPs, and related molecules are being introduced clinically. Results in knockout mice further identified MMP-12 as a dominant contributor to this activity, a finding that is in line with recent comprehensive systems-level approaches (43). The sensor also offers the advantage of in vivo detection by virtue of its wholebody distribution, NIRF, and substrate-dependent activation.…”

“…Proteinases produced by eosinophils include various MMPs, some of which have been involved in the pathology of asthma (36). A systemslevel approach integrating a gene expression compendium of microarray data sets from multiple sources identified MMP-12 as the only MMP that was persistently upregulated in lungs upon induction of OVA-derived allergic airway inflammation (43). MMP-12 may be a central enzyme produced by eosinophils because it is also expressed at high levels in patients with airway inflammation (33,44,45).…”

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“…Only transcripts with Entrez Gene IDs were included in analysis. Statistical analysis was performed using the ScoreGenes gene expression package (http://www.cs.huji.ac.il/labs/ compbio/scoregenes), and data visualization was performed using Genomica (http://genomica.weizmann.ac.il/) and Spotfire Decision Site 8.0 (Spotfire, Gö teborg, Sweden) (29). The complete set of gene array data has been deposited in the Gene Expression Omnibus database with GEO serial accession number GSE10921 (http://www.ncbi.nlm.…”

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