Disease-Specific Gene Expression Profiling in Multiple Models of Lung Disease

Abstract

Rationale: Microarray technology is widely employed for studying the molecular mechanisms underlying complex diseases. However, analyses of individual diseases or models of diseases frequently yield extensive lists of differentially expressed genes with uncertain relationships to disease pathogenesis. Objectives: To compare gene expression changes in a heterogeneous set of lung disease models in order to identify common gene expression changes seen in diverse forms of lung pathology, as well as relatively small subsets of genes likely to be involved in specific pathophysiological processes. Methods: We profiled lung gene expression in 12 mouse models of infection, allergy, and lung injury. A linear model was used to estimate transcript expression changes for each model, and hierarchical clustering was used to compare expression patterns between models. Selected expression changes were verified by quantitative polymerase chain reaction. Measurements and Main Results: A total of 24 transcripts, including many involved in inflammation and immune activation, were differentially expressed in a substantial majority (9 or more) of the models. Expression patterns distinguished three groups of models: (1) bacterial infection (n 5 5), with changes in 89 transcripts, including many related to nuclear factor-kB signaling, cytokines, chemokines, and their receptors; (2) bleomycin-induced diseases (n 5 2), with changes in 53 transcripts, including many related to matrix remodeling and Wnt signaling; and (3) T helper cell type 2 (allergic) inflammation (n 5 5), with changes in 26 transcripts, including many encoding epithelial secreted molecules, ion channels, and transporters. Conclusions: This multimodel dataset highlights novel genes likely involved in various pathophysiological processes and will be a valuable resource for the investigation of molecular mechanisms underlying lung disease pathogenesis.

Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis

“…The well-characterized model of bleomycin-induced lung injury has been extensively used to investigate potential pathways involved in the pathogenesis of pulmonary fibrosis and to explore therapeutic approaches (22). Despite some limitations with regard to recapitulation of human disease, a number of pathways that are up-regulated in IPF (e.g., TGF-β and Wnt/β-catenin) are also up-regulated following bleomycin (28). As reviewed in ref.…”

Blockade of the Wnt/.BETA.-Catenin Pathway Attenuates Bleomycin-Induced Pulmonary Fibrosis

“…Inflammation has been suggested to have a very limited involvement in the pathogenesis of pulmonary fibrosis (Mapel et al 1996;Selman et al 2001), and the role of Wnt signaling in lung inflammation has largely been unexplored. Based on a comparison of the gene expression profiles in different mouse models of infection, allergy, and lung injury, Lewis et al (2008) found the regulation of the Wnt signaling pathway in only one mouse model of bleomycin-induced lung fibrosis, and not in any other inflammatory lung disease model (Lewis et al 2008).…”

Regulation and function of miRNA-21 in health and disease

“…MiRNAs may play an important role in asthma as it is characterized by marked changes in gene and protein expression in the lung. 68,69 By using three different experimental animal models of asthma viz, OVA (ovalbumin), Aspergillus fumigatus, lung specific-IL-13 overexpression, Lu et al 70 have shown that IL-12p35 (a component of IL-12) expression is downregulated during asthma, which is correlated with increased expression of miR-21. Subsequent analyses have shown that miR-21 was primarily detected in the cytoplasm of mononuclear expression of miR-21 under Nestin (a protein marker for neural stem cells, also expressed in adult haematopoietic cells) promoter control.…”