Novel genes in Human Asthma Based on a Mouse Model of Allergic Airway Inflammation and Human Investigations (original) (raw)
Related papers
Gene expression profile of ovalbumin-induced lung inflammation in a murine model of asthma
Journal of investigational allergology & clinical immunology, 2008
Asthma is a chronic inflammatory disease that is associated with airway hyperresponsiveness, tissue remodeling, and airway obstruction, and that involves coordinate expression of multiple inflammatory genes in the lungs. To evaluate the gene expression pattern in a mouse model of asthma and assess the effect of a new drug, R142571, on the gene expression profile. Lung tissue from ovalbumin-sensitized mice was used to examine gene expression on the CodeLink oligonucleotide mouse 20 K bioarray platform. Data were validated for some genes by semiquantitative reverse-transcriptase polymerase chain reaction. Of the 19,736 genes represented on the microarray, expression of 378 genes was differentially regulated (215 upregulated and 163 downregulated), with at least a 2-fold change in expression (P <.05). The differentially regulated transcripts included genes known to be involved in several different biological processes, including signaling, DNA-dependent transcriptional regulation, i...
Quantitative Trait Loci Controlling Allergen-Induced Airway Hyperresponsiveness in Inbred Mice
American Journal of Respiratory Cell and Molecular Biology, 2000
Identification of the genetic loci underlying asthma in humans has been hampered by variability in clinical phenotype, uncontrolled environmental influences, and genetic heterogeneity. To circumvent these complications, the genetic regulation of asthma-associated phenotypes was studied in a murine model. We characterized the strain distribution patterns for the asthma-related phenotypes airway hyperresponsiveness (AHR), lung eosinophils, and ovalbumin (OVA)-specific serum immunoglobulin (Ig) E induced by allergen exposure protocols in A/J, AKR/J, BALB/cJ, C3H/HeJ, and C57BL/6J inbred strains and in (C3H/HeJ ϫ A/J)F1 mice. Expression of AHR differed between strains and was sometimes discordant with lung eosinophils or serum IgE. Furthermore, we identified two distinct quantitative trait loci (QTL) for susceptibility to allergeninduced AHR, Abhr1 (allergen-induced bronchial hyperresponsiveness) (lod ϭ 4.2) and Abhr2 (lod ϭ 3.7), on chromosome 2 in backcross progeny from A/J and C3H/HeJ mice. In addition, a QTL on chromosome 7 was suggestive of linkage to this trait. These QTL differ from those we have previously found to control noninflammatory AHR in the same crosses. Elucidation of the genes underlying these QTL will facilitate the identification of biochemical pathways regulating AHR in animal models of asthma and may provide insights into the pathogenesis of human disease. Materials and Methods Animals Studies were performed in age-matched, virus-free, male mice obtained from Jackson Laboratory (Bar Harbor, ME) at 4 wk of age and allowed to acclimate for 1 to 2 wk before experimentation. A/J (n ϭ 94), AKR/J (n ϭ 5), BALB/cJ (n ϭ 5), C57BL/6J (n ϭ 7), C3H/HeJ (n ϭ 99), (C3H/HeJ ϫ A/J)F1 (n ϭ 39), (A/J ϫ C3H/ HeJ)F1 (n ϭ 5), [A/J ϫ (C3H/HeJ ϫ A/J)F1] backcross (n ϭ 780), [(C3H/HeJ ϫ A/J)F1 ϫ A/J] backcross (n ϭ 58), [C3H/HeJ ϫ (C3H/HeJ ϫ A/J)F1] backcross (n ϭ 124), and [(C3H/HeJ ϫ A/J)F1 ϫ (C3H/HeJ ϫ A/J)F1]F2 (n ϭ 128) mice were studied. No differences in the range or trends of allergen-induced AHR were seen between [A/J ϫ (C3H/HeJ ϫ A/J)F1] and [(C3H/HeJ ϫ A/J)F1 ϫ A/J] backcross mice, so these groups were combined and are referred to collectively as A/J backcross mice. Animals were housed under high-efficiency particulate absolute (HEPA) laminar flow hoods in an environmentally controlled facility and allowed free access to ovalbumin (OVA)-free rodent chow and water.
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...
Mouse genetic model for antigen-induced airway manifestations of asthma
Genes and Immunity, 2007
Allergic asthma is a genetically complex disease characterized by allergen-specific immunoglobulin (Ig)E, eosinophilic inflammation of the lungs and airway hyper-responsiveness to bronchospasmogenic stimuli. In this study, we compared 13 recombinant congenic (RC) mouse strains in an ovalbumin model of allergic asthma. Different intensities and types of responses are observed throughout the RC strains. Intensities range from resistance to asthma in CcS05, to a very severe bronchoconstrictive reaction upon methacholine challenge for the parental STS strain. All strains show a 'modified' Th2 response except CcS14, which shows a 'true' Th2 response. When data from all strains are pooled, airway reactivity shows significant correlations with the serum Ig levels and the levels of interleukin (IL)-4, IL-5 and IL-13 in the broncho-alveolar lavage (BAL), at low dosage of methacholine (below 25 mg/ml), whereas at high dosage airway reactivity only correlates with BAL neutrophil levels. This indicates that at least two different mechanisms are involved in the airway reactivity to methacholine. None of these correlations can be found in every individual strain, which demonstrates that the asthma traits in this mouse model are genetically dissociated and that the loci can be genetically mapped.
Thorax, 1998
Background-Existing murine models of asthma lack many of the inflammatory and epithelial changes that are typical of the human disease. Moreover, these models are frequently complicated by allergic alveolitis. Methods-High IgE responder BALB/c mice were systemically sensitised to ovalbumin and chronically challenged with low particle mass concentrations of aerosolised ovalbumin. Titres of antiovalbumin IgE in serum were measured at two weekly intervals by enzyme immunoassay, accumulation of inflammatory cells and histopathological abnormalities of the epithelium were quantified morphometrically in the trachea and the lungs, and airway reactivity was assessed by measuring bronchoconstriction following intravenous administration of methacholine. Results-Mice sensitised by two intraperitoneal injections of ovalbumin developed high titres of IgE antibodies to ovalbumin. Following exposure to low concentrations of aerosolised antigen for up to eight weeks these animals developed a progressive inflammatory response in the airways, characterised by the presence of intraepithelial eosinophils and by infiltration of the lamina propria with lymphoid/ mononuclear cells, without associated alveolitis.
The American Journal of Pathology, 2011
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.
Allergen-induced airway disease is mouse strain dependent
American journal of physiology. Lung cellular and molecular physiology, 2003
We investigated the development of airway hyperreactivity (AHR) and inflammation in the lungs of nine genetically diverse inbred strains of mice [129/SvIm, A/J, BALB/cJ, BTBR+(T)/tf/tf, CAST/Ei, C3H/HeJ, C57BL/6J, DBA/2J, and FVB/NJ] after sensitization and challenge with ovalbumin (OVA). At 24, 48, and 72 h post-OVA exposure, the severity of AHR and eosinophilic inflammation of the mouse strains ranged from relatively unresponsive to responsive. The severity of the airway eosinophilia of some strains did not clearly correlate with the development of AHR. The temporal presence of T helper type 2 cytokines in lung lavage fluid also varied markedly among the strains. The levels of IL-4 and IL-13 were generally increased in the strains with the highest airway eosinophilia at 24 and 72 h postexposure, respectively; the levels of IL-5 were significantly increased in most of the strains with airway inflammation over the 72-h time period. The differences of physiological and biological res...
International Archives of Allergy and Immunology, 2011
gen-specific IgG 1 antibodies did not differ between ⌬ D-DFL and wild type. Following challenge with aerosolized allergen, a marked local T H 2 cytokine response and an eosinophilic airway inflammation developed. Quantitative histology revealed increased mucus production and intense goblet cell metaplasia which were identical to those in wild type. Moreover, ⌬ D-DFL mice developed an airway hyperreactivity to methacholine and to the specific allergen, which both did not differ from those in wild-type animals. Conclusion: A single D H gene segment is sufficient for the establishment of the asthma phenotype in a murine model of allergic airway inflammation. Thus, the allergic phenotype depends on the amino acid composition and not on the diversity of the classical antigen-binding site.