Dissecting asthma using focused transgenic modeling and functional genomics.
BACKGROUND
Asthma functional genomics studies are challenging because it is difficult to relate gene expression changes to specific disease mechanisms or pathophysiologic features. Use of simplified model systems might help to address this problem. One such model is the IL-13/Epi (IL-13-overexpressing transgenic mice with STAT6 expression limited to epithelial cells) focused transgenic mouse, which isolates the effects of a single mediator, IL-13, on a single cell type, the airway epithelial cell. These mice develop airway hyperreactivity and mucus overproduction but not airway inflammation.


OBJECTIVE
To identify how effects of IL-13 on airway epithelial cells contribute to gene expression changes in murine asthma models and determine whether similar changes are seen in people with asthma.


METHODS
We analyzed gene expression in ovalbumin allergic mice, IL-13-overexpressing mice, and IL-13/Epi mice with microarrays. We analyzed the expression of human orthologues of genes identified in the mouse studies in airway epithelial cells from subjects with asthma and control subjects.


RESULTS
In comparison with the other 2 models, IL-13/Epi mice had a remarkably small subset of gene expression changes. Human orthologues of some genes identified as increased in the mouse models were more highly expressed in airway epithelial cells from subjects with asthma than in controls. These included calcium-activated chloride channel 1, 15-lipoxygenase, trefoil factor 2, and intelectin.


CONCLUSIONS
The combination of focused transgenic models, DNA microarray analyses, and translational studies provides a powerful approach for analyzing the contributions of specific mediators and cell types and for focusing attention on a limited number of genes associated with specific pathophysiologic aspects of asthma.
Kuperman
Douglas A
DA
Department of Medicine, Allergy-Immunology Division, Northwestern University Feinberg School of Medicine, Chicago, USA.
Lewis
Christina C
CC
Woodruff
Prescott G
PG
Rodriguez
Madeleine W
MW
Yang
Yee Hwa
YH
Dolganov
Gregory M
GM
Fahy
John V
JV
Erle
David J
DJ
D000818:Animals; D001249:Asthma / Q000235:genetics*; D001980:Bronchi / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines; D058851:GPI-Linked Proteins; D020869:Gene Expression Profiling; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology; D037102:Lectins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D000071164:Trefoil Factor-2
D016207:Cytokines; D058851:GPI-Linked Proteins; C432397:ITLN1 protein, human; D018793:Interleukin-13; D037102:Lectins; C000604007:TFF2 protein, human; D000071164:Trefoil Factor-2